α-Tertiary Amines en Route to Natural Products 9780128222621

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a-TERTIARY AMINES EN ROUTE TO NATURAL PRODUCTS

VISUAL GUIDES TO NATURAL PRODUCT SYNTHESIS SERIES

a-TERTIARY AMINES EN ROUTE TO NATURAL PRODUCTS ABDUL HAMEED MARIYA AL-RASHIDA MUHAMMAD RAZA SHAH

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-822262-1 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

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Contents Preface

xi

1. Natural products with a-tertiary amine

1

2. Altemicidin

5

1.1 Abstract References

2.1 Abstract 2.2 Kende’s first total (
)-altemicidin synthesis 2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0] framework (2008) 2.4 Kan’s total synthesis of SB-203207: an altemicidin’s analogue (2014) 2.5 Hayakawa’s studies toward altemicidin’s analogue (SB-203207) References

1 3

5 6 7

8 9 10

3. Amathaspiramides AeF

11

4. Cephalotaxine

19

3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8

Abstract Trauner’s first total synthesis of (
)-amathaspiramide F (2002) Ohfune’s (
)-total synthesis of (
)-amathaspiramide F (2008) Fukuyama’s total syntheses of (
)-amathaspiramides (2012) Tambar’s formal synthesis of ()-amathaspiramide F (2013) Lee’s synthesis of amathaspiramide C (2015) Sun’s synthesis of amathaspiramides B, D, and F (2016) Kim’s synthesis of (
)-amathaspiramide F (2018) References

Abstract Biosynthesis Weinreb’s first total ()-cephalotaxine synthesis (1975) Semmelhack’s total synthesis of cephalotaxine (1975) Hanaoka’s first-generation ()-total synthesis (1986) Hanaoka’s second-generation formal synthesis (1988) Kuehne’s total synthesis (1988) Fuchs’s total synthesis of ()-cephalotaxine (1988)

v

11 11 13 13 13 15 15 15 18

19 20 20 20 21 22 22 23

vi

Contents

4.9 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 4.18 4.19 4.20 4.21 4.22 4.23 4.24 4.25 4.26 4.27 4.28 4.29 4.30 4.31 4.32 4.33 4.34 4.35 4.36 4.37 4.38 4.39 4.40 4.41 4.42 4.43

Ikeda’s total racemic synthesis (1990/1993) Mori’s asymmetric (
)-cephalotaxine synthesis (1995) Mariano’s synthesis via two interrelated strategies (1996) Nagasaka’s synthesis of (
)-cephalotaxine (1997) El Bialy’s formal synthesis (1998) Ikeda’s formal synthesis (1999) Tietze’s synthetic approach (1999) Nagasaka’s synthesis (2002) Yoshida’s formal synthesis (2002) Li’s synthesis (2003) Royer’s synthesis via semipinacolic rearrangement (2004) Li’s second-generation formal synthesis (2005) Li’s synthesis of DolbyeWeinreb enamine Mariano’s formal synthesis via photocyclization reaction (2006) Gin’s synthetic studies (2006) Li’s formal synthesis (2007) Stoltz’s formal synthesis via Pd-catalyzed aerobic oxidative heterocyclization chemistry (2007) Ishibashi’s total synthesis (2008) Hayes’s first formal synthesis (2008) Hayes’s second formal synthesis via 1,5-CH insertion reaction (2008) Bubnov’s approach toward cephalotaxine (2008) Liu’s formal synthesis (2009) Zhang synthesis (2009) Li’s total synthesis (2011) Tu’s (
)-formal synthesis (2012) Renaud’s (
)-formal synthesis (2012) Zhang-Liu’s formal synthesis (2012) Jiang’s formal synthesis (2013) Huang’s formal synthesis (2013) Huang’s formal synthesis (2015) Hong’s formal synthesis (2015) Chandrasekhar’s formal total synthesis (2016) Fan’s total synthesis (2017) Beaudry’s (
)-total synthesis via furan oxidationetransannular Mannich cyclization (2019) Kim’s formal (
)-total synthesis (2019) References

5. Kaitocephalin 5.1 5.2 5.3 5.4

Abstract Kitahara’s total synthesis (2002) Kitahara’s total synthesis (2002) Ohfune’s total enantioselective synthesis (2005)

23 23 24 25 25 25 26 27 27 27 28 28 29 29 30 30 31 31 31 32 32 33 33 33 34 34 34 35 36 36 37 38 39 41 41 63

67 67 68 68 68

Contents

5.5 5.6 5.7 5.8 5.9 5.10 5.11 5.12

Chamberlin’s total synthesis (2008) Ohfune’s total enantioselective synthesis (2009) Ma’s reinvestigation of kaitocephalin (2011) Hatakeyama’s total synthesis (2012) Kang’s kaitocephalin total synthesis (2013) Garner’s synthesis via [C þ NC þ C] coupling (2014) Dhavale’s formal synthesis (2014) Lee’s total synthesis (2019) References

6. Lactacystin 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 6.20 6.21 6.22 6.23 6.24 6.25 6.26

Abstract Biosynthesis of lactacystin Corey’s first total synthesis of (þ)-lactacystin (1992) Corey’s revised synthesis (1998) Corey’s second-generation synthesis (1998) Corey’s synthesis of a-methylomuralide (2003) ˜ mura’s (þ)-total synthesis (1993/1996) Smith-O Baldwin’s (þ)-total synthesis (1994) Chida’s (þ)-total synthesis (1997) Kang’s formal synthesis (1998) Adams clasto-lactacystin synthesis (1999) Panek Total Synthesis (1999) Ohfune synthesis (2000) Pattenden’s formal synthesis (2003) Hatakeyama’s total synthesis (2004) Donohoe’s racemic synthesis (2004) Wardrop’s formal synthesis (2005) Jacobsen’s total synthesis (2006) Shibasaki’s total synthesis (2006) Hayes’s total synthesis via 1,5-CH insertion (2008) Hayes’s formal synthesis (2010) Silverman’s total synthesis (2011) Inoue’s total synthesis (2015) Chandrasekhar’s formal synthesis (2019) Page’s formal synthesis (2019) Poisson’s (
)-omuralide synthesis (2019) References

7. Salinosporamide A 7.1 7.2 7.3 7.4 7.5 7.6

Abstract Corey’s first total synthesis of salinosporamide A (2004) Second-generation improved synthesis (2005) Danishefsky enantioselective synthesis (2005) Pattenden racemic synthesis (2006) Lam’s formal synthesis (2008)

vii 68 69 69 69 72 76 77 78 79

81

81 82 83 83 83 83 83 84 84 85 85 85 86 86 87 87 87 87 88 88 89 89 89 90 90 90 102

105

105 106 107 108 109 109

viii 7.7 7.8 7.9 7.10 7.11 7.12 7.13 7.14

Contents

Romo’s asymmetric total synthesis (2011) Ling’s formal synthesis (2010) Fukuyama’s total synthesis (2011) Chida’s total synthesis (2011) Lannou’s approach (2012) Burton’s (
)-formal synthesis (2014) Gonda’s approach (2016) Burton’s total synthesis (2018) References

8. Manzacidins

8.1 Ohfune’s total synthesis of manzacidin A and C (2000) 8.2 Du Bois’ enantioselective manzacidins A and C syntheses (2002) 8.3 Mackay’s ()-manzacidin D synthesis (2004) 8.4 Lanter’s manzacidin C synthesis (2005) 8.5 Maruoka’s manzacidins A synthesis (2005) 8.6 Deng’s formal synthesis of manzacidin A via tandem conjugate additioneprotonation (2006) 8.7 Sibi’s manzacidin A synthesis (2007) 8.8 Ohfune’s synthesis of manzacidin B (2007) 8.9 Leighton’s manzacidin C synthesis (2008) 8.10 Ohfune’s manzacidins A and C synthesis (2008) 8.11 Mohapatra’s synthesis of manzacidin B (2012) 8.12 Ohfune’s synthesis of manzacidin B (2012) 8.13 Kawabata’s manzacidin A synthesis (2013) 8.14 Ichikawa’s manzacidins A and C synthesis (2012) 8.15 Inoue’s manzacidin A synthesis (2015) 8.16 Sakakura’s synthesis of mazacidins A and C (2017) 8.17 Ukaji’s formal synthesis of manzacidin (2017) 8.18 Renata’s formal synthesis of manzacidin C (2018) References

9. Neooxazolomycin

9.1 Kende’s first enantioselective total neooxazolomycin synthesis (1990) 9.2 Hatakeyama‘s total neooxazolomycin synthesis (2007) 9.3 Hatakeyama‘s total oxazolomycin synthesis (2011) 9.4 Pattenden’s approach toward oxazolomycin A and neooxazolomycin synthesis (2007) 9.5 Moloney’s approach toward oxazolomycin (2002) 9.6 Taylor’s formal synthesis of (þ)-neooxazolomycin (2011) 9.7 Mohapatra‘s approach toward oxazolomycin (2006) 9.8 Donohoe‘s approach toward pyrrolidinone core of oxazolomycin A (2012) References

110 111 112 113 114 114 115 116 117

119 120 121 122 122 123 124 125 125 127 128 129 130 131 132 133 134 135 136 136

139 140 141 142 143 144 145 146 147 148

Contents

ix

10. Sphingofungins

149

11. (
)-FR901483 and TAN1251 (A-D)

167

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 10.10 10.11 10.12 10.13 10.14 10.15 10.16 10.17

Abstract Kobayashi’s asymmetric synthesis of sphingofungin F (1998) Trost’s total synthesis of sphingofungin F (1998) Trost’s total synthesis of sphingofungin F (2001) Trost’s total synthesis of sphingofungin E (2001) Lin’s total synthesis of sphingofungin F (2000) Shiozaki’s total synthesis of sphingofungin E (2001) Lin’s total synthesis of sphingofungin E (2001) Chida’s total synthesis of sphingofungin E (2002) Chida’s total synthesis of sphingofungin E (2002) Ham’s total synthesis of sphingofungin F (2002) Hayes’s approach toward sphingofungin E (2006) Xu’s total synthesis of sphingofungin F (2010) Martinkova´’s total synthesis of sphingofungin E (2010) Kan’s total synthesis of sphingofungin E (2013) Chida’s total synthesis of sphingofungin F (2015) Yakura’s total synthesis of sphingofungin E (2017) References

11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 11.10 11.11 11.12 11.13 11.14 11.15 11.16

Abstract Proposed biosynthesis of FR901483 and TAN1251 Sinder’s total synthesis of (
)-FR901483 (1999) Sorensen’s synthesis via oxidative cyclization (2000) Ciufolini’s synthesis via oxidative cyclization (2001) Funk’s total synthesis (2001) Wardrop’s formal synthesis of ()-desmethylamino FR901483 (2001) Fukuyama’s total synthesis (2004) Brummond’s formal synthesis (2005) Kerr’s total synthesis via ring-opening/annulation reaction (2009) Fukuyama’s intermediate synthesis of FR901483 (2010) Bonjoch’s tricyclic skeleton of FR901483 (2003) Weinreb’s studies toward total synthesis (2006) Reissig’s approach toward azaspirane core of FR901483 (2006) Huang’s formal enantioselective synthesis of (
)-FR901483 (2012) Huang’s enantioselective total syntheses of (
)-FR901483 and (þ)-8-epi-FR901483 (2013) 11.17 Gaunt’s syntheses of (
)-FR901483 and (þ)-TAN1251C (2019) References

12. Synthetic approach to the TAN1251 alkaloids 12.1 12.2 12.3 12.4 12.5

Kawahara’s total synthesis of TAN1251A (2002) Kawahara’s total synthesis of (
)-TAN1251A (2002) Wardrop’s formal synthesis of (
)-TAN1251A (2001) Snider’s biomimetic total syntheses of TAN1251AeD (2000) Ciufolini’s approach via oxidative cyclization (2001)

149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 165

167 168 168 171 172 173 174 175 176 177 178 179 180 180 181 182 184 185

187

187 188 189 190 192

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Contents

12.6 Honda’s formal synthesis (
)-TAN1251A (2002) 12.7 Honda’s enantiospecific total synthesis of TAN1251C and D (2002) 12.8 Hayes’s enantioselective total synthesis of (
)-TAN1251A (2000) 12.9 Peiqiang’s enantioselective synthesis key core of TAN1251C 12.10 Kan’s total synthesis of TAN1251C (2017) References

13. (1S,3R)-1-Aminocyclopentane-1,3-diarboxylic acid (ACPD)

13.1 Abstract 13.2 Ma’s total synthesis of (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid (1997) 13.3 Hodgson’s total (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid synthesis via hydroboration 13.4 Hayes’s total (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid synthesis via 1,5-CH insertion References

14. Tetrodotoxin 14.1 14.2 14.3 14.4 14.5 14.6

14.7 14.8 14.9 14.10

Index

Abstract Du Bois’s stereoselective synthesis of (
)-tetrodotoxin (2003) Isobe’s first asymmetric total synthesis (2003) Isobe’s efficient total synthesis of tetrodotoxin (2004) Sato’s stereocontrolled synthesis of ()-tetrodotoxin (2005) Ohfune’s synthesis of (
)-5,6,11-trideoxytetrodotoxin and its 4-epimer (2006) Sato’s stereoselective synthesis of tetrodotoxin (2007) Nishikawa’s synthesis of (
)-5,11-dideoxytetrodotoxin (2013) Ciufolin’s formal synthesis of ()-tetrodotoxin (2015) Fukuyama’s total synthesis of (
)-tetrodotoxin (2017) References

193 194 195 196 197 198

199

199

200 200 201 201

203

203 203 204 204 206

206 206 208 219 220 221

223

Preface To date, Nature continues to be the greatest reservoir of astonishingly diverse array of structural diversity observed in chemical space; interestingly a lot of this chemical space is speculated to be yet unexplored. All living organisms including the microbes synthesize a plethora of biologically active compounds de novo in their cells and tissues. These active molecules are vital for sustenance of life and associated delicate ecosystems. Since the beginning, it has been the deepest desire of man to harness this power of nature for therapeutic intervention and prevention of diseases. A significant chunk of modern medicinal and pharmaceutical chemistry is based on either pure natural products or synthetic compounds having scaffolds inspired and derived from the natural products. Hence, natural products, by virtue of their vast structural diversity, continue to hold the fascination of synthetic chemists. Herein, we propose a book series that will cover the area of total synthesis of natural products. The multistep syntheses of natural products will be presented in easy-to-grasp schemes, highlighting the key steps involved in synthetic layout. This visual guide will provide a quick and easy way to read and to understand the new/novel synthetic strategies to construct the whole structural framework of natural products. The visual guide on natural products synthesis will deliver express access to read and understand the synthetic strategies. Volume I will cover the class of natural products bearing a-tertiary amine motif. Some of the examples of such natural products include altemicidin, amathaspiramide (AeF), kaitocephalin, lactacystin, salinosporamide, manzacidins, neooxazolomycin, sphingofungins, (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid (ACPD), and tetrodotoxin. These molecules have gained much popularity among synthetic chemists. A large number of synthetic approaches and total syntheses of these molecules have been published. Thus, the collection of natural product syntheses in this book will provide a quick and an easy access to the readers to get the gist of synthetic route toward the targeted natural products.

xi

C H A P T E R

1

Natural products with a-tertiary amine 1.1 Abstract Natural products isolated from various sources such as plants, marine life forms, fungus, algae, and bacteria have been the greatest source of design inspiration for synthesis of biologically active molecules and drugs targeting various diseases. These natural products provide an almost unlimited source of biologically active unique molecules and novel scaffolds. These molecules are constantly being synthesized de novo, inside the living cells, and serve various purposes from simple survival to growth and defense. Such molecules serve as a design template for synthetic chemists and medicinal chemists for the synthesis of molecules with specific biological activities. Most of the drugs available in the market are based on natural products. Alkaloids are a unique class of natural products that have been vital in the development of drugs against various diseases (Fig. 1.1). It has long been the quest of synthetic organic chemistry to come up with the design and experiments for in-lab synthesis of naturally occurring molecules and their derivatives. Although the staggering structural complexity and multiple stereocenters in alkaloids have proved to be a challenge from synthetic chemistry point of view, this structural diversity is responsible for the activity of these molecules against various biological targets, hence their potential to treat different diseases. On the basis of structural diversity, alkaloids have been classified into different groups, among which the natural products bearing a-tertiary amine moiety have attracted considerable attention from the synthetic community. Among the pool of natural products having N-quaternary center, we have selected the most popular natural products such as

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00001-9

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1. Natural products with a-tertiary amine O Me

HHN CO H 2

N

O

SO2NH2

OH

O

C N D H E HO OMe Cephalotaxine

OH

O

H NH2

O A O

N R

N H

Br

Br Amathaspiramides

B

Altemicidin Cl

Cl

O

OH

HO H N

Cl

H CO2H

O

N H HO

CO2H NH2

O

N H

CO2H

Kaitocephalin

O

OH S

NHAc

O OH

N H

H

O CO2H

Lactacystin

Salinosporamide A Br

HN N H

O

O

N 5

4

CO2H

H2N HO2C

CO2H H2N

ACPD

OH O Manzacidin B

HO H N N H HO

OO OH

OH

Tetrodotoxin O O

OH

OH

N

O

OH NH2 R R = Me, CH2OH

OH

O OH HO

OH

O

O

N

N H

OH Neooxazolomycin

Sphingofungins

HO

O

OMe N HO O (HO)2P O

N

NHMe H HCl

(–)-FR901483

O

N R O R = H, TAN1251A R = OH, TAN1251B

FIGURE 1.1 Structures of different natural products containing a-tert-alkylamino carbon

center.

References

3

altemicidin, amathaspiramides, cephalotaxine, kaitocephalin, lactacystin, salinosporamide, manzacidines, tetradoxtin, neooxazolomycin, sphingofungins, ACPD, TAN1251A & B, and ( )-FR901483 with diverse enantioand diaseteroselective methodologies to construct tetra-substituted carbon center surrounded by three carbons and one nitrogen atom, i.e., a-tertalkylamino carbon center1 or in case of bearing acid moiety, termed as a,adisubstituted-a-amino acid.2

References 1. (a) Mailyan, A. K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu, P.; Zakarian, A. CuttingEdge and Time-Honored Strategies for Stereoselective Construction of CeN Bonds in Total Synthesis. Chem. Rev. 2016, 116, 4441e4557. (b) Kang, S. H.; Kang, S. Y.; Lee, H.-S.; Buglass, A. J. Total Synthesis of Natural Tert-Alkylamino Hydroxy Carboxylic Acids. Chem. Rev. 2005, 105, 4537e4558. 2. Ohfune, Y.; Shinada, T. Enantio and Diastereoselective Construction of a, a-disubstituted a-amino Acids for the Synthesis of Biologically Active Compounds. Eur. J. Org Chem. 2005, 2005, 5127e5143.

C H A P T E R

2

Altemicidin 2.1 Abstract ( )-Altemicidin is an interesting naturally occurring 6-azainden monoterpene sulfonamide alkaloid that exhibits strong inhibition against tumor cells and has potent acaricidal activity. ( )-Altemicidin 1 was isolated by Takahashi research group in 1989 from the actinomycete strain Streptomyces sioyaensis.1 The acylated structure of the altemicidin showed strong inhibitory activity against isoleucyl, leucyl, and valyl tRNA synthetase.2 The interesting biological properties and complex structural features of ( )-altemicidin make it an attractive target for synthetic organic chemists (Fig. 2). The structural features of altemicidin include a core 6-azainden ring, b-hydroxy group at C-2 position, and key a,a-dialkyl-a-amino acid moiety at C-1 position. So far, only three synthetic approaches toward this alkaloid have been reported. The first enantioselective total synthesis of altemicidin was carried out by Kende’s group via DielseAlder reaction to construct C-1 N-bearing quaternary center and PotierePolonovski rearrangement in the synthetic sequence. Later, Kan’s group built the stereocontrolled core framework of altemicidin as an advanced intermediate. Further, the Kan’s group competed the total synthesis of altemicidin derivative SB-203202 via desymmetrical C H insertion reaction and Curtius rearrangement in an enantioselective way. The schematic outlook of all approaches has been presented in the coming section.

FIGURE 2 Structure of altemicidin.

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2. Altemicidin

2.2 Kende’s first total (L)-altemicidin synthesis See (Scheme 1).

SCHEME 1

Total synthesis of ( )-altemicidin via PotierePolonovski rearrangement.3

2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0] framework (2008)

2.3 Kan’s approach toward altemicidin Bicyclo[3.3.0] framework (2008) See (Scheme 2).

SCHEME 2

Stereocontrolled construction of altemicidin core framework.4

7

8

2. Altemicidin

2.4 Kan’s total synthesis of SB-203207: an altemicidin’s analogue (2014) See (Scheme 3).

SCHEME 3

Total synthesis of altemicidin’s analog (of SB-203207).5

2.5 Hayakawa’s studies toward altemicidin’s analogue (SB-203207)

9

2.5 Hayakawa’s studies toward altemicidin’s analogue (SB-203207) See (Scheme 4).

SCHEME 4 Altemicidin’s analog: formation of four contiguous nitrogen-containing stereogenic centers.6

10

2. Altemicidin

References 1. Takahashi, A.; Kurasawa, S.; Ikeda, D.; Okami, Y.; Takeuchi, T. Altemicidin, a New Acaricidal and Antitumor Substance. J. Antibiot. 1989, 42, 1556e1561. 2. (a) Banwell, M. G.; Crasto, C. F.; Easton, C. J.; Forrest, A. K.; Karoli, T.; March, D. R.; Mensah, L.; Nairn, M. R.; O’Hanlon, P. J.; Oldham, M. D. Analogues of SB-203207 as Inhibitors of tRNA Synthetases. Bioorg. Med. Chem. Lett 2000, 10, 2263e2266. (b) Houge-Frydrych, C. S. V.; Gilpin, M. L.; Skett, P. W.; Tyler, J. W. SB-203207 and SB-203208, Two Novel Isoleucyl tRNA Synthetase Inhibitors from a Streptomyces Sp. J. Antibiot. 2000, 53, 364e372. 3. (a) Kende, A. S.; Liu, K.; Jos Brands, K. Total Synthesis of (-)-Altemicidin: A Novel Exploitation of the Potier-Polonovski Rearrangement. J. Am. Chem. Soc. 1995, 117, 10597e10598. and references therein. (b) Kende, A. S.; Brands, K.; Blass, B. A Novel Dyatropic Rearrangement of g-N,N-dibenzylamino a,b-dehydro N-Formylamino Acid Esters. Tetrahedron Lett. 1993, 34, 579e582. 4. Kan, T.; Kawamoto, Y.; Asakawa, T.; Furuta, T.; Fukuyama, T. Synthetic Studies on Altemicidin: Stereocontrolled Construction of the Core Framework. Org. Lett. 2008, 10, 169e171. and references therein. (i) Kan, T.; Inoue, T.; Kawamoto, Y.; Yonehara, M.; Fukuyama, T. A Novel Synthesis of Bicyclo [3.3.0] Octane Ring System via a Desymmetric CH Insertion Reaction. Synlett 2006, 1583e1585, 2006. 5. Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y.; Furuta, T.; Asakawa, T.; Inai, M.; Wakimoto, T.; Fukuyama, T.; Kan, T. Enantioselective Synthesis of SB-203207. Org. Lett. 2014, 16, 1646e1649. 6. Hayakawa, I.; Nagayasu, A.; Sakakura, A. Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers. J. Org. Chem. 2019, 84, 15614e15623.

C H A P T E R

3

Amathaspiramides AeF 3.1 Abstract The amathaspiramides AeF are a class of marine alkaloids that have been isolated from a New Zealand collection of the bryozoan Amathia wilsoni by Prinsep and Morris.1 The core of these alkaloids is a highly functionalized aza-spirobicyclic structural framework possessing a-tertalkylamino carbon center and a hemiaminal center. The amathaspiramides have exhibited excellent bioactivities as antiviral and antimicrobial agents, albeit with moderate cytotoxicity. This family of structurally complex natural products has attracted significant attention from the synthetic chemists. There are many different synthetic methodologies reported for total synthesis of different members of amathaspiramides AeF. Trauner and Ohfune completed the total synthesis of amathaspiramide F, whereas Fukuyama completed the total synthesis of AeF in a stereoselective way. The Tambar’s group reported synthesis of amathaspiramide F, whereas Lee et al. completed total synthesis of amathaspiramide C; formal synthesis of AeF was reported via Fukuyama’s route. Recently, Sun’s group reported the synthesis of amathaspiramides B, D, and F in an asymmetric way (Fig. 3).

3.2 Trauner’s first total synthesis of (L)-amathaspiramide F (2002) See (Scheme 5).

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3. Amathaspiramides AeF

FIGURE 3

Structures of amathaspiramides AeF.

SCHEME 5 Total synthesis of (
)-amathaspiramide F via Micheal addition.2

13

3.5 Tambar’s formal synthesis of ()-amathaspiramide F (2013)

3.3 Ohfune’s (L)-total synthesis of (L)-amathaspiramide F (2008) See (Scheme 6).

3.4 Fukuyama’s total syntheses of (L)-amathaspiramides (2012) See (Scheme 7).

3.5 Tambar’s formal synthesis of (±)-amathaspiramide F (2013) See (Scheme 8).

I OMOM

a) PhSNH-tBu OH NCS; b) (+)-DIP-Cl -40 °C, 70% (2 steps) TBS

OH

OH TBS

PdCl2(PPh3)2 CuI, 73%

TBS

MOMO

MOMO BCl (+)-DIP-Cl = 2

a) PdCl2(PPh3)2, nBu3SnH b) AcOH, MeOH c) Boc-homoallylglycine EDCI, DMAP, 59% (3 steps)

a) OsO4, NMO b) NaIO4; c) NaBH3CN d) p-TsOH; e) TFAA MeO2C f) Ozonlysis g) MeN(TMS)2 TBS 20% (7 steps) O O

CF3 N

Me N HO HO

O

i) LDA (4 equiv) NHBoc O ZnCl2 (1.2 equiv) NH THF, -78 °C to RT Boc ii) then CH2N2, 88% TBS MOMO Claisen rearrangement erythro/threo (dr = 7:1)

a) nBu4NBrCl2 b) MeI, K2CO3 c) LiBH4, 53% (3 steps)

(-)-Amathaspiramide F

Total synthesis of (-)-Amathaspiramide F with overall yield 1.3% in 17 steps [ α]D24 –39.0 (c 0.30, MeOH)

SCHEME 6 Total synthesis via Claisen rearrangement.3

OMOM

14

3. Amathaspiramides AeF

SCHEME 7

Total syntheses of (
)-amathaspiramides via Micheal addition.4

3.8 Kim’s synthesis of (
)-amathaspiramide F (2018)

SCHEME 8

15

Formal synthesis of ()-amathaspiramide F via [2,3]-Stevens rearrangement.5

3.6 Lee’s synthesis of amathaspiramide C (2015) See (Scheme 9).

3.7 Sun’s synthesis of amathaspiramides B, D, and F (2016) See (Scheme 10).

3.8 Kim’s synthesis of (L)-amathaspiramide F (2018) See (Scheme 11).

16

3. Amathaspiramides AeF

OTBS

Path I MeO2C Br MeO

Aldehyde O

Br

Br

MeO

MeO

a) LDA, MePh2SiCl b) LDA, Aldehyde, MeO2C Br -78 oC; HCl; c) TsCl

Br Li

-78 oC

N2

Br

MeO2C

TMS

TMS N N

[3+2] Cycloaddition OTs Path II Br MeO

d) TsOH; e) HCO2H f) PPh3, DIAD g) DIBAL, -78 oC 13% (7 steps)

Br MeO Br

MeO2C

Br

Li

TMS -78 oC

O N H

N2

Me O Amathaspiramide C

CO2Et [3+2] Cycloaddition

Br

Br MeO

MeO

MeO2C

Br

MeO2C

O

Br SiMe3

SiMe3 N N Li OEt

N

N N O

Total Amathaspiramide C Steps = 7 Overall Yield = 13%

a) p-TsOH, 95% b) HOOH, 66% c) MeOH, DBAD, PS-PPh3, sonication, 58%.

Br MeO Br O

N Steps H Fukuyama's route (2012) O

Amathaspiramide A-F

SCHEME 9 Amathaspiramide C via [3 þ 2]-cycloaddition.6

N Me

3.8 Kim’s synthesis of (
)-amathaspiramide F (2018)

SCHEME 10 Amathaspiramides B, D, and F via aza-Barbier Allylation.

17

18

3. Amathaspiramides AeF

SCHEME 11 (
)-Amathaspiramide F via asymmetric Ca-alkylation of proline.7

References 1. Morris, B. D.; Prinsep, M. R.; Amathaspiramides, A.
F. Novel Brominated Alkaloids from the Marine Bryozoan Amathia Wilsoni. J. Nat. Prod. 1999, 62, 688e693. 2. Hughes, C. C.; Trauner, D. The Total Synthesis of (
)-Amathaspiramide F. Angew. Chem. Int. Ed. 2002, 41, 4556e4559. and references therein. i) Moss, W. O.; Jones, A. C.; Wisedale, R.; Mahon, M. F.; Molloy, K. C.; Bradbury, R. H.; Hales, N. J.; Gallagher, T. 2-Amino Ketene S, S-Acetals as a-amino Acid Homoenolate Equivalents. Synthesis of 3-substituted Prolines and Molecular Structure of 2-(n-Pivaloylpyrrolidin-2-Ylidene)-1, 3-dithiane. J. Chem. Soc. Perkin Trans. 1992, 1, 2615e2624. 3. Sakaguchi, K.; Ayabe, M.; Watanabe, Y.; Okada, T.; Kawamura, K.; Shinada, T.; Ohfune, Y. Total Synthesis of (
)-amathaspiramide F, Tetrahedron 2009, 65, 10355e10364. Sakaguchi, K.; Ayabe, M.; Watanabe, Y.; Okada, T.; Kawamura, K.; Shiada, T.; Ohfune, Y. Total synthesis of (
)-amathaspiramide F, Org. Lett. 2008, 10, 5449-5452. 4. Chiyoda, K.; Shimokawa, J.; Fukuyama, T. Total Syntheses of All the Amathaspiramides. Angew. Chem. Int. Ed. 2012, 124, 2555e2558. 5. Soheili, A.; Tambar, U. K. Synthesis of ()-amathaspiramide F and Discovery of an Unusual Stereocontrolling Element for the [2, 3]-Stevens Rearrangement. Org. Lett. 2013, 15, 5138e5141. 6. O’Connor, M.; Sun, C.; Lee, D. Synthesis of Amathaspiramides by Aminocyanation of Enoates. Angew. Chem. Int. Ed. 2015, 54, 9963e9966. 7. Cho, H.; Shin, J. E.; Lee, S.; Jeon, H.; Park, S.; Kim, S. Asymmetric Ca-Alkylation of Proline via Chirality Transfers of Conformationally Restricted Proline Derivative: Application to the Total Synthesis of (
)-Amathaspiramide. F. Org. Lett. 2018, 20, 6121e6125.

C H A P T E R

4

Cephalotaxine 4.1 Abstract Cephalotaxine (CET) is a parent polycyclic scaffold for the class of Cephalotaxus alkaloids.1 The ester derivatives of CET, i.e., harringtonine (2), isoharringtonine (3), homoharringtonine (4), and deoxyharringtonine (5) show important anticancer activity against different types of leukemia (Fig. 4).2 In 1963, Paudler and his coworker3 isolated it from Cephalotaxus drupacea and Cephalotaxus fortunei. Later on, the stereochemistry of CET was established by Powell et al.4,5 via X-ray crystallography. The natural product (CET) possesses unique structural framework that consists of pentacyclic ring system with three contiguous stereogenic centers. The presence of quaternary center next to nitrogen is one of the key synthetic challenges in the synthesis of this CET. The interesting structural features of natural product and prominent biological activities of its ester derivatives make it attractive synthetic target for chemists to develop novel synthetic strategies and efficient synthetic routes.

FIGURE 4 Structures of cephalotaxine and its ester derivatives.

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00004-4

19

© 2021 Elsevier Inc. All rights reserved.

20

4. Cephalotaxine

4.2 Biosynthesis See (Scheme 12).

4.3 Weinreb’s first total (±)-cephalotaxine synthesis (1975) See (Scheme 13). • Lewis acid [BF3•(Et2O)2] catalyzes cyclization to closed sevenmembered benzazepine ring. • Magnesium catalyzed intramolecular Michael reaction to furnish pentacycle (
)-demethylcephalotaxine.

4.4 Semmelhack’s total synthesis of cephalotaxine (1975) See (Scheme 14).

SCHEME 12

Biosynthesis of cephalotaxine.6

4.5 Hanaoka’s first-generation (
)-total synthesis (1986)

SCHEME 13

First total (
)-cephalotaxine synthesis.7

4.5 Hanaoka’s first-generation (±)-total synthesis (1986) See (Scheme 15).

21

22

4. Cephalotaxine

SCHEME 14

Total synthesis of cephalotaxine, a convergent strategy.8

4.6 Hanaoka’s second-generation formal synthesis (1988) See (Scheme 16).

4.7 Kuehne’s total synthesis (1988) See (Scheme 17).

4.10 Mori’s asymmetric ()-cephalotaxine synthesis (1995)

23

SCHEME 15 Cephalotaxine (
)-total synthesis via Claisen rearrangement.9

4.8 Fuchs’s total synthesis of (±)-cephalotaxine (1988) See (Scheme 18).

4.9 Ikeda’s total racemic synthesis (1990/1993) See (Scheme 19).

4.10 Mori’s asymmetric (L)-cephalotaxine synthesis (1995) See (Scheme 20).

24

4. Cephalotaxine

SCHEME 16 Second-generation formal synthesis of cephalotaxine.10

4.11 Mariano’s synthesis via two interrelated strategies (1996) (I) Single-electron transfer (SET)epromoted photocyclization See (Scheme 21). (II) Transannular cyclization approach See (Scheme 22).

4.14 Ikeda’s formal synthesis (1999)

SCHEME 17

Total synthesis via novel oxidative rearrangement.11

4.12 Nagasaka’s synthesis of (L)-cephalotaxine (1997) See (Scheme 23).

4.13 El Bialy’s formal synthesis (1998) See (Scheme 24).

4.14 Ikeda’s formal synthesis (1999) See (Scheme 25).

25

26

4. Cephalotaxine

SCHEME 18 Total synthesis via intramolecular Hetero DielseAlder reaction.12

4.15 Tietze’s synthetic approach (1999) See (Scheme 26). • Heck reaction by using Hermanto’s catalyst21 to form the benzazepine ring and to complete pentacycle.

4.18 Li’s synthesis (2003)

SCHEME 19 Synthesis via acid-catalyzed Pummerer rearrangement.13

4.16 Nagasaka’s synthesis (2002) See (Scheme 27).

4.17 Yoshida’s formal synthesis (2002) See (Scheme 28).

4.18 Li’s synthesis (2003) (I) Via transannular reductive rearrangement See (Scheme 29).

27

28

4. Cephalotaxine

SCHEME 20 First asymmetric synthesis of ()-cephalotaxine via alkylation by employing Seebach-type14 chemistry.15

(II) Via unusual azo-Nazarov-type cyclization See (Scheme 30).

4.19 Royer’s synthesis via semipinacolic rearrangement (2004) See (Scheme 31).

4.20 Li’s second-generation formal synthesis (2005) See (Scheme 32).

4.22 Mariano’s formal synthesis via photocyclization reaction (2006)

29

I) Single-Electron-Transfer (SET) promoted photocyclisation

SCHEME 21

Synthetic route toward cephalotaxine synthesis.

4.21 Li’s synthesis of DolbyeWeinreb enamine See (Scheme 33).

4.22 Mariano’s formal synthesis via photocyclization reaction (2006) See (Scheme 34). See (Scheme 35).

30

4. Cephalotaxine

II) Transannular cyclisation Approach

SCHEME 22

Two interrelated strategies toward cephalotaxine synthesis.16,17

4.23 Gin’s synthetic studies (2006) See (Scheme 36).

4.24 Li’s formal synthesis (2007) See (Scheme 37).

4.27 Hayes’s first formal synthesis (2008)

SCHEME 23

31

()-Cephalotaxine synthesis via enantiomers separation.18

4.25 Stoltz’s formal synthesis via Pd-catalyzed aerobic oxidative heterocyclization chemistry (2007) See (Scheme 38).

4.26 Ishibashi’s total synthesis (2008) See (Scheme 39).

4.27 Hayes’s first formal synthesis (2008) See (Scheme 40).

32

4. Cephalotaxine

SCHEME 24 Formal total synthesis of ()-cephalotaxine.19

4.28 Hayes’s second formal synthesis via 1,5-CH insertion reaction (2008) See (Scheme 41).

4.29 Bubnov’s approach toward cephalotaxine (2008)33 See (Scheme 42).

4.32 Li’s total synthesis (2011)

33

SCHEME 25 Cephalotaxine formal synthesis via Pummerer rearrangement reaction.19

4.30 Liu’s formal synthesis (2009) See (Scheme 43). See (Scheme 44).

4.31 Zhang synthesis (2009) See (Scheme 45).

4.32 Li’s total synthesis (2011) See (Scheme 46).

34

4. Cephalotaxine

SCHEME 26

Cephalotaxine’ synthesis via palladium-catalyzed transformations.20

4.33 Tu’s (L)-formal synthesis (2012) See (Scheme 47).

4.34 Renaud’s (L)-formal synthesis (2012) See (Scheme 48).

4.35 Zhang-Liu’s formal synthesis (2012) See (Scheme 49). See (Scheme 50).

4.36 Jiang’s formal synthesis (2013)

SCHEME 27

35

Cephalotaxine synthesis via tertiary N-acyliminium ion chemistry.18

4.36 Jiang’s formal synthesis (2013) See (Scheme 51).

36

4. Cephalotaxine

SCHEME 28

Cephalotaxine formal synthesis.22

4.37 Huang’s formal synthesis (2013) See (Scheme 52).

4.38 Huang’s formal synthesis (2015) See (Scheme 53).

4.39 Hong’s formal synthesis (2015)

I) Via transannular reductive rearrangement

SCHEME 29

Cephalotaxine synthesis.23

4.39 Hong’s formal synthesis (2015) See (Scheme 54).

37

38

4. Cephalotaxine

II) Via unusual azo-Nazarov-type cyclization

SCHEME 30

Cephalotaxine via unusual azo-Nazarov-type cyclization.

4.40 Chandrasekhar’s formal total synthesis (2016) See (Scheme 55).

4.41 Fan’s total synthesis (2017)

SCHEME 31

Cephalotaxine synthesis via semipinacolic rearrangement.24

4.41 Fan’s total synthesis (2017) See (Scheme 56).

39

40

4. Cephalotaxine

SCHEME 32

SCHEME 33

Cephalotaxine formal synthesis.25

Synthesis of DolbyeWeinreb enamine.26

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 34

Cephalotaxine formal synthesis via photocyclization reaction.27

4.42 Beaudry’s (L)-total synthesis via furan oxidationetransannular Mannich cyclization (2019) See (Scheme 57).

4.43 Kim’s formal (L)-total synthesis (2019) See (Scheme 58).

41

42

4. Cephalotaxine

SCHEME 35

SCHEME 36

Synthetic pathway II.

Synthesis via strain-released rearrangement of N-vinyl-2-arylaziridines.28

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 37

SCHEME 38

43

Formal synthesis via FriedeleCrafts cyclization.29

Synthesis via Pd-catalyzed aerobic oxidative heterocyclization chemistry.30

44

4. Cephalotaxine

SCHEME 39

Total synthesis via radical cascade cyclization reactions.19

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 40

Formal synthesis via 1,5-CH insertion reaction.31

45

46

4. Cephalotaxine

SCHEME 41

Formal synthesis via 1,5-CH insertion reaction.32

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 42 Approach toward cephalotaxine via FriedeleCrafts cyclization.

47

48

SCHEME 43

4. Cephalotaxine

Formal synthesis via [2,3]-Stevens rearrangementdacid lactonization.34

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 44

Second synthetic route.

49

50

4. Cephalotaxine

SCHEME 45 Synthesis via intermolecular Schmidt reaction.35

4.43 Kim’s formal ()-total synthesis (2019)

51

SCHEME 46 Total synthesis via oxy-Nazarov cyclization and transannulation

strategies.36

52

SCHEME 47

ment reaction.37

4. Cephalotaxine

()-Formal synthesis via tandem hydroamination/semipinacol rearrange-

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 48

()-Formal synthesis via stereoselective radical carboazidation.38

53

54

4. Cephalotaxine

SCHEME 49

Formal synthesis of cephalotaxine via double alkylation.39

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 50 Parallel synthetic route.

SCHEME 51

Formal synthesis via Pauson-Khand reaction.40

55

56

4. Cephalotaxine

SCHEME 52 Formal synthesis via reductive gem-bis-alkylation.41

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 53

Formal synthesis via nitroso-ene cyclization.42

57

58

4. Cephalotaxine

SCHEME 54

Formal synthesis via N-iminium ion cyclization.43

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 55 Formal total synthesis via Aryne insertion reaction.44

59

60

4. Cephalotaxine

SCHEME 56

Total synthesis via Au-catalyzed [2 þ 3] annulation reaction.45

4.43 Kim’s formal ()-total synthesis (2019)

SCHEME 57

Synthesis via furan oxidationetransannular Mannich cyclization.46

61

62

SCHEME 58

(EECR).47

4. Cephalotaxine

Formal ()-total synthesis via proline ester enolate Claisen rearrangement

References

63

References 1. (a) Jalil Miah, M. A.; Hudlicky, T.; Reed, J. W. In The Alkaloids, Vol., Cordell, G. A., Ed.; Acadmic Press: San Diego, 1998; pp. 199e269. (b) Huang, L.; Xue, X. In The Alkaloids, Vol. 23, Brossi, A., Ed.; Academic Press: New York, 1984. 2. Powell, R.; Weisleder, D.; Smith, C., Jr. Antitumor Alkaloids from Cephalotaxus Harringtonia: Structure and Activity. J. Pharmacol. Sci. 1972, 61, 1227e1230. 3. Paudler, W. W.; Kerley, G. I.; McKay, J. The Alkaloids of Cephalotaxus Drupacea and Cephalotaxus Fortunei. J. Org. Chem. 1963, 28, 2194e2197. 4. Powell, R.; Weisleder, D.; Smith, C.; Wolff, I.; Haylett, T.; Swart, L. Structure of Cephalotaxine and Related Alkaloids. Tetrahedron Lett. 1969, 46, 4081e4084, 2679101. 5. Arora, S.; Bates, R.; Grady, R.; Powell, R. Crystal and Molecular Structure of Cephalotaxine P-Bromobenzoate. J. Org. Chem. 1974, 39, 1269e1271. 6. Parry, R. J.; Chang, M. N. T.; Schwab, J. M.; Foxman, B. M. Biosynthesis of the Cephalotaxus Alkaloids. Investigations of the Early and Late Stages of Cephalotaxine Biosynthesis. J. Am. Chem. Soc. 1980, 102, 1099e1111. 7. Weinreb, S. M.; Auerbach, J. Total Synthesis of the Cephalotaxus Alkaloids. Cephalotaxine, Cephalotaxinone, and Demethylcephalotaxinone. J. Am. Chem. Soc. 1975, 97, 2503. 8. Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. Total Synthesis of the Cephalotaxus Alkaloids. Problem in Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 1975, 97, 2507e2516. 9. Yasuda, S.; Yamada, T.; Hanaoka, M. A Novel and Stereoselective Synthesis of (
)-cephalotaxine and its Analogue. Tetrahedron Lett. 1986, 27, 2023e2026. 10. Yasuda, S.; Yamamoto, Y.; Yoshida, S.; Hanaoka, M. A Total Synthesis of (
)-cephalotaxinamide. Chem. Pharm. Bull. 1988, 36, 4229e4231. 11. Kuehne, M. E.; Bornmann, W. G.; Parsons, W. H.; Spitzer, T. D.; Blount, J. F.; Zubieta, J. J. Total Syntheses of (
)-Cephalotaxine and (
)-8-Oxocephalotaxin. J. Am. Chem. Soc. 1988, 53, 3439e3450. 12. Burkholder, T.; Fuchs, P. Total Synthesis of Dl-Cephalotaxine: the First Example of an Intramolecular 4þ2 Cycloaddition where the Dienophile Has Been Delivered from the Face Opposite to the Tethering Moiety. J. Am. Chem. Soc. 1988, 110, 2341e2342. 13. (a) Ishibashi, H.; Okano, M.; Tamaki, H.; Maruyama, K.; Yakura, T.; Ikeda, M. Total Synthesis of (
)-cephalotaxine. J. Chem. Soc., Chem. Commun. 1990, 20, 1436e1437. (b) Ikeda, M.; Okano, M.; Kosaka, K.; Kido, M.; Ishibashi, H. Synthetic Studies on Cephalotaxus Alkaloids. A Synthesis of (
)-cephalotaxine. Chem. Pharm. Bull. 1993, 41, 276e281. 14. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. Alkylation of Amino Acids without Loss of the Optical Activity: Preparation of. alpha.-substituted Proline Derivatives. A Case of Self-Reproduction of Chirality. J. Am. Chem. Soc. 1983, 105, 5390e5398. 15. Isono, N.; Mori, M. Total Synthesis of (-)-cephalotaxine. J. Org. Chem. 1995, 60, 115e119. 16. a) Lin, X.; Kavash, R. W.; Mariano, P. S. Two Interrelated Strategies for Cephalotaxine Synthesis. J. Org. Chem. 1996, 61, 7335e7347. b) Lin, X.; Kavash, R. W.; Mariano, P. S. A Cephalotaxine Synthesis Founded on a Mechanistically Interesting, Quasi-Biomimetic Strategy. J. Am. Chem. Soc. 1994, 116, 9791e9792. 17. a) Lin, X.; Kavash, R. W.; Mariano, P. S. Two Interrelated Strategies for Cephalotaxine Synthesis. J. Org. Chem. 1996, 61, 7335e7347. b) Lin, X.; Kavash, R. W.; Mariano, P. S. A Cephalotaxine Synthesis Founded on a Mechanistically Interesting, Quasi-Biomimetic Strategy. J. Am. Chem. Soc. 1994, 116, 9791e9792.

64

4. Cephalotaxine

18. Nagasaka, T.; Sato, H.; Saeki, S.-i. 1-Azaspiro [4.4] Nonane-2, 6-dione and the Separation and Absolute Configurations of its Enantiomers. Tetrahedron: Asymmetry 1997, 8, 191e194. 19. Ikeda, M.; El Bialy, S. A.; Hirose, K.-i.; Kotake, M.; Bayomi, S. M.; Shehata, I. A.; Abdelal, A. M.; Yakura, T. A Formal Total Synthesis of (-)-cephalotaxine. Chem. Pharm. Bull. 1999, 47, 983e987. 20. Tietze, L. F.; Schirok, H. Enantioselective Highly Efficient Synthesis of (-)-cephalotaxine Using Two Palladium-Catalyzed Transformations. J. Am. Chem. Soc. 1999, 121, 10264e10269. ¨ fele, K.; Beller, M. Pal21. Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Riermeier, T. H.; O ladacycles: Efficient New Catalysts for the Heck Vinylation of Aryl Halides. Chem. Eur J. 1997, 3, 1357e1364. 22. Suga, S.; Watanabe, M.; Yoshida, J. Electroauxiliary-assisted Sequential Introduction of Two Carbon Nucleophiles on the Same Alpha-Carbon of Nitrogen: Application to the Synthesis of Spiro Compounds. J. Am. Chem. Soc. 2002, 124, 14824e14825. 23. Li, W. D.; Wang, Y. Q. A Novel and Efficient Total Synthesis of Cephalotaxine. Org. Lett. 2003, 5, 2931e2934. 24. Planas, L.; Pe´rard-Viret, J.; Royer, J. Stereoselective Synthesis of ()-Cephalotaxine and C-7 Alkylated Analogues. J. Org. Chem. 2004, 69, 3087e3092. 25. Li, W. D.; Ma, B. C. A Novel Formal Total Synthesis of Cephalotaxine. J. Org. Chem. 2005, 70, 3277e3280. 26. Ma, B. C.; Wang, Y. Q.; Li, W. D. An alternative synthesis of Dolby-Weinreb enamine en route to cephalotaxine. J. Org. Chem. 2005, 70, 4528e4530. 27. Zhao, Z.; Mariano, P. S. Application of the Photocyclization Reaction of 1, 2-CyclopentaFused Pyridinium Perchlorate to Formal Total Syntheses of ()-cephalotaxine. Tetrahedron 2006, 62, 7266e7273. 28. Eckelbarger, J. D.; Wilmot, J. T.; Gin, D. Y. Strain-release Rearrangement of N-Vinyl-2Arylaziridines. Total Synthesis of the Anti-leukemia Alkaloid ()-deoxyharringtonine. J. Am. Chem. Soc. 2006, 128, 10370e10371. 29. Li, W. D.; Wang, X. W. Novel Formal Synthesis of Cephalotaxine via a Facile FriedelCrafts Cyclization. Org. Lett. 2007, 9, 1211e1214. 30. Liu, Q.; Ferreira, E. M.; Stoltz, B. M. Convergency and Divergency as Strategic Elements in Total Synthesis: The Total Synthesis of ()-Drupacine and the Formal Total Synthesis of (
)-Cephalotaxine, ()-Cephalotaxine, and (þ)-Cephalotaxine. J. Org. Chem. 2007, 72 (19), 7352e7358. 31. Esmieu, W. R.; Worden, S. M.; Catterick, D.; Wilson, C.; Hayes, C. J. A Formal Synthesis of (-)-cephalotaxine. Org. Lett. 2008, 10, 3045e3048. 32. Hameed, A.; Blake, A. J.; Hayes, C. J. A Second Generation Formal Synthesis of ()-cephalotaxine. J. Org. Chem. 2008, 73, 8045e8048. 33. Kuznetsov, N. Y.; Kolomnikova, G. D.; Khrustalev, V. N.; Golovanov, D. G.; Bubnov, Y. N. The Combination of Diallylboration and Ring-Closing Metathesis in the Synthesis of Spiro-b-Amino Alcohols and (
)-Cephalotaxine. Eur. J. Org Chem. 2008, 2008, 5647e5655. 34. Sun, M.-r.; Lu, H.-t.; Wang, Y.-z.; Yang, H.; Liu, H.-m. Highly Efficient Formal Synthesis of Cephalotaxine, Using the Stevens RearrangementAcid Lactonization Sequence as A Key Transformation. J. Org. Chem. 2009, 74, 2213e2216. 35. Zhao, Y. M.; Gu, P.; Zhang, H. J.; Zhang, Q. W.; Fan, C. A.; Tu, Y. Q.; Zhang, F. M. Formal Syntheses of (þ/-)-stemonamine and (þ/-)-cephalotaxine. J. Org. Chem. 2009, 74, 3211e3213. 36. Li, W.-D. Z.; Duo, W.-G.; Zhuang, C.-H. Concise Total Synthesis of (
)-Cephalotaxine via a Transannulation Strategy: Development of a Facile Reductive Oxy-Nazarov Cyclization. Org. Lett. 2011, 13, 3538e3541.

References

65

37. Zhang, Q. W.; Xiang, K.; Tu, Y. Q.; Zhang, S. Y.; Zhang, X. M.; Zhao, Y. M.; Zhang, T. C. Formal Synthesis of ()-Cephalotaxine Based on a Tandem Hydroamination/Semipinacol Rearrangement Reaction. Chem. Asian J. 2012, 7, 894e898. 38. Gonc¸alves-Martin, M. G.; Zigmantas, S.; Renaud, P. Formal Synthesis of ()-Cephalotaxine. Helv. Chim. Acta 2012, 95, 2502e2514. 39. Zhang, Z.-W.; Zhang, X.-F.; Feng, J.; Yang, Y.-H.; Wang, C.-C.; Feng, J.-C.; Liu, S. Formal Synthesis of Cephalotaxine. J. Org. Chem. 2012, 78, 786e790. 40. Xing, P.; Huang, Z.-g.; Jin, Y.; Jiang, B. A Formal Synthesis of (
)-Cephalotaxine via PausoneKhand Reaction. Synthesis 2013, 45, 596e600. 41. Xiao, K. J.; Luo, J. M.; Xia, X. E.; Wang, Y.; Huang, P. Q. General One-Pot Reductive gemBis-Alkylation of Tertiary Lactams/Amides: Rapid Construction of 1-Azaspirocycles and Formal Total Synthesis of (
)-Cephalotaxine. Chem. Eur J. 2013, 19, 13075e13086. 42. Huang, S.-H.; Tian, X.; Mi, X.; Wang, Y.; Hong, R. Nitroso-ene Cyclization Enabled Access to 1-azaspiro [4.4] Nonane and its Application in a Modular Synthesis toward (
)-cephalotaxine. Tetrahedron Lett. 2015, 56, 6656e6658. 43. Liu, H.; Yu, J.; Li, X.; Yan, R.; Xiao, J.-C.; Hong, R. Stereoselectivity in N-Iminium Ion Cyclization: Development of an Efficient Synthesis of (
)-Cephalotaxine. Org. Lett. 2015, 17, 4444e4447. 44. Gouthami, P.; Chegondi, R.; Chandrasekhar, S. Formal Total Synthesis of (
)-Cephalotaxine and Congeners via Aryne Insertion Reaction. Org. Lett. 2016, 18, 2044e2046. 45. Ma, X.-Y.; An, X.-T.; Zhao, X.-H.; Du, J.-Y.; Deng, Y.-H.; Zhang, X.-Z.; Fan, C.-A. AuCatalyzed [2þ3] Annulation of Enamides with Propargyl Esters: Total Synthesis of Cephalotaxine and Cephalezomine H. Org. Lett. 2017, 19, 2965e2968. 46. Ju, X.; Beaudry, C. M. Total Synthesis of ()-Cephalotaxine and ()-Homoharringtonine via Furan OxidationeTransannular Mannich Cyclization. Angew. Chem. Int. Ed. 2019, 58, 6752e6755. 47. Jeon, H.; Chung, Y.; Kim, S. Proline Ester Enolate Claisen Rearrangement and Formal Total Synthesis of (e)-Cephalotaxine. J. Org. Chem. 2019, 84, 8080e8089.

C H A P T E R

5

Kaitocephalin 5.1 Abstract Kaitocephalin, a novel pyrrolidine-based amino acid, was isolated by Shin-ya et al. in 1997 from the filamentous fungus Eupenicillium shearii.1 The structural framework of the molecules showed the conjugation of three amino acids include alanine, proline, and serine via carbonecarbon linkages. The natural product has challenging synthetic features that include the construction of central trisubstituted proline core possessing N-bearing quaternary center at C4 position. Initially, the stereochemistry of natural product was proposed (2S,3S,4R,7R,9S) on the basis of NMR data [2];2 however, the structure was later revised to (2R,3S,4R,7R,9S) based on synthetic studies [3].3 The biological evaluation of kaitocephalin showed strong antagonist activity against 2-amino-3-(3-hydroxy-5methylisoxazole-4-ylpropionate (AMPA), kainic acid (KA)4 [4], and Nmethyl-D-aspartate (NMDA) glutamate receptors, which have key role in various physiological processes such as learning, memory, and neural plasticity [5].5 Thus, the pharmaceutically important antagonist can serve as lead for the development of new therapeutic agent to treat neurological diseases. The fascinating structural framework and significantly biological potential encourage and drag the attention of chemists in the relevant area to synthesize molecule for further processes followed to develop new drug molecules (Fig. 5).

FIGURE 5

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00005-6

Structures of kaitocephalin.

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5. Kaitocephalin

5.2 Kitahara’s total synthesis (2002) See (Scheme 59).

5.3 Kitahara’s total synthesis (2002) See (Scheme 60).

5.4 Ohfune’s total enantioselective synthesis (2005) See (Scheme 61).

5.5 Chamberlin’s total synthesis (2008) See (Scheme 62).

SCHEME 59

Total synthesis of proposed structure.3

5.8 Hatakeyama’s total synthesis (2012)

SCHEME 60 Total synthesis of revised structure.6

5.6 Ohfune’s total enantioselective synthesis (2009) See (Scheme 63).

5.7 Ma’s reinvestigation of kaitocephalin (2011) See (Scheme 64).

5.8 Hatakeyama’s total synthesis (2012) See (Scheme 65).

69

70

5. Kaitocephalin

SCHEME 61

Total enantioselective synthesis.7

5.8 Hatakeyama’s total synthesis (2012)

SCHEME 62 Stereocontrolled total synthesis.8

71

72

5. Kaitocephalin

SCHEME 63

Total enantioselective synthesis.9

5.9 Kang’s kaitocephalin total synthesis (2013) See (Scheme 66).

5.9 Kang’s kaitocephalin total synthesis (2013)

SCHEME 64

Reinvestigation of kaitocephalin.10

73

74

5. Kaitocephalin

SCHEME 65

Synthesis via Rh-catalyzed CH amination.11

5.9 Kang’s kaitocephalin total synthesis (2013)

SCHEME 66

Kaitocephalin total synthesis.12

75

76

5. Kaitocephalin

5.10 Garner’s synthesis via [C D NC D C] coupling (2014) See (Scheme 67).

SCHEME 67

Synthesis via [C þ NC þ C] coupling.13

5.11 Dhavale’s formal synthesis (2014)

5.11 Dhavale’s formal synthesis (2014) See (Scheme 68).

SCHEME 68

Formal synthesis.14

77

78

5. Kaitocephalin

5.12 Lee’s total synthesis (2019) See (Scheme 69).

SCHEME 69

Total synthesis.15

References

79

References 1. Shin-Ya, K.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H. Structure of Kaitocephalin, a Novel Glutamate Receptor Antagonist Produced by Eupenicillium shearii. Tetrahedron Lett. 1997, 38, 7079e7082. 2. Kobayashi, H.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Absolute Configuration of a Novel Glutamate Receptor Antagonist Kaitocephalin. Tetrahedron Lett. 2001, 42, 4021e4023. 3. Okue, M.; Kobayashi, H.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.; Watanabe, H.; Kitahara, T. Synthesis of the Proposed Structure and Revision of Stereochemistry of Kaitocephalin. Tetrahedron Lett. 2002, 43, 857e860. 4. Shin-Ya, K. Novel Antitumor and Neuroprotective Substances Discovered by Characteristic Screenings Based on Specific Molecular Targets. Biosci. Biotechnol. Biochem. 2005, 69, 867e872. 5. Limon, A.; Reyes-Ruiz, J. M.; Vaswani, R. G.; Chamberlin, A. R.; Miledi, R. Kaitocephalin Antagonism of Glutamate Receptors Expressed in Xenopus Oocytes. ACS Chem. Neurosci. 2010, 1, 175e181. 6. Watanabe, H.; Okue, M.; Kobayashi, H.; Kitahara, T. The First Synthesis of Kaitocephalin Based on the Structure Revision. Tetrahedron Lett. 2002, 43, 861e864. 7. Kawasaki, M.; Shinada, T.; Hamada, M.; Ohfune, Y. Total Synthesis of ()-kaitocephalin. Org. Lett. 2005, 7, 4165e4167. 8. Vaswani, R. G.; Chamberlin, A. R. Stereocontrolled Total Synthesis of ()-kaitocephalin. J. Org. Chem. 2008, 73, 1661e1681. 9. Hamada, M.; Shinada, T.; Ohfune, Y. Efficient Total Synthesis of ()-kaitocephalin. Org. Lett. 2009, 11, 4664e4667. 10. Yu, S.; Zhu, S.; Pan, X.; Yang, J.; Ma, D. Reinvestigation on Total Synthesis of Kaitocephalin and its Isomers. Tetrahedron 2011, 67, 1673e1680. 11. Takahashi, K.; Yamaguchi, D.; Ishihara, J.; Hatakeyama, S. Total Synthesis of ()-Kaitocephalin Based on a Rh-Catalyzed CeH Amination. Org. Lett. 2012, 14, 1644e1647. 12. Lee, W.; Youn, J.-H.; Kang, S. H. Total Synthesis of ()-kaitocephalin. Chem. Commun. 2013, 49 (45), 5231e5233. 13. Garner, P.; Weerasinghe, L.; Van Houten, I.; Hu, J. A Concise [Cþ NCþ CC] CouplingEnabled Synthesis of Kaitocephalin. Chem. Commun. 2014, 50, 4908e4910. 14. Markad, P. R.; Rohokale, R. S.; Pawar, N. J.; Dhavale, D. D. D-glucose Based Synthesis of ProlineeSerine CeC Linked Central and Right Hand Core of a Kaitocephalin-A Glutamate Receptor Antagonist. RSC Adv. 2015, 5, 81162e81167. 15. Lee, W. Desymmetrization-initiated Stereocontrolled Synthesis of ()-Kaitocephalin. Asian J. Org. Chem. 2019, 8, 1687e1697.

C H A P T E R

6

Lactacystin 6.1 Abstract (þ)-Lactacystin, pyrrolidinone-based secondary metabolite, was isolated by Omura et al.1 from the Streptomyces species (Fig. 6). The natural product served as a potent and selective proteasome inhibitor, which plays an important role in cellular protein degradation, an essential process in living cells2 to regulate the cell cycle, cell division, regulation of transcription factors, etc. However, any irregularity in the proteasome functions leads to human disease, i.e., malignancies and neurodegenerative disorders. Subsequently, the inhibition of proteasome provides a significant opportunity to treat proteasome-related diseases such as arthritis, asthma, and Alzheimer’s disease.3 The structural framework of molecules showed the presence of g-lactam ring linked with N-acetyl-L-cysteine moiety via thioester bond. The natural product bears four contiguous chiral center, among which nitrogen-bearing quaternary center is a synthetic challenge for organic chemists. Upon the elimination of cysteine residue, the natural product converted into active form b-lactone (also known omuralide) via lactonization. The ()-clasto-lactacystin (omuralide) upon hydrolysis converted into inactive dihydroxy acid, while, when enters the cell, it acylates

FIGURE 6 Structure of lactacystin.

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6. Lactacystin

FIGURE 7 Proteasome inhibition via ()-clasto-lactacystin.6

the proteasome to inhibit its function. Moreover, the ()-clasto-lactacystin also conjugates with glutathione by thiol ester to act as reservoir for lactacystin active form, omuralide4,5 (Fig. 7).

6.2 Biosynthesis of lactacystin • The biosynthetic pathway of lactacystin was proposed by Nakagawa and coworkers.7 • Key precursors are isobutyric acid, L-leucine, and L-cysteine in lactacystin biosynthetic pathway. • Key reaction involves (1) intramolecular cyclization, (2) hydroxylation of C9 carbon atom, and (3) coupling of L-cysteine 7 to afford lactacystin (Scheme 70).

˜ mura’s (þ)-total synthesis (1993/1996) 6.7 Smith-O

SCHEME 70

Biosynthesis of lactacystin.

6.3 Corey’s first total synthesis of (D)-lactacystin (1992) See (Scheme 71).

6.4 Corey’s revised synthesis (1998) See (Scheme 72).

6.5 Corey’s second-generation synthesis (1998) See (Scheme 73).

6.6 Corey’s synthesis of a-methylomuralide (2003) See (Scheme 74).

˜ mura’s (D)-total synthesis (1993/1996) 6.7 Smith-O See (Scheme 75).

83

84

6. Lactacystin

SCHEME 71 Total synthesis of (þ)-lactacystin.8

6.8 Baldwin’s (D)-total synthesis (1994) See (Scheme 76).

6.9 Chida’s (D)-total synthesis (1997) See (Scheme 77).

SCHEME 72

Revised synthesis of lactacystin.9

6.12 Panek Total Synthesis (1999)

SCHEME 73

Synthesis via late-stage isopropyl group installation.10

6.10 Kang’s formal synthesis (1998) See (Scheme 78).

6.11 Adams clasto-lactacystin synthesis (1999) See (Scheme 79).

6.12 Panek Total Synthesis (1999) See (Scheme 80).

85

86

6. Lactacystin

SCHEME 74

Synthesis of a-methylomuralide (2003)11 and different analogs.12

6.13 Ohfune synthesis (2000) See (Scheme 81).

6.14 Pattenden’s formal synthesis (2003) See (Scheme 82).

6.18 Jacobsen’s total synthesis (2006)

SCHEME 75 Total synthesis of lactacystin.13

6.15 Hatakeyama’s total synthesis (2004) See (Scheme 83).

6.16 Donohoe’s racemic synthesis (2004) See (Scheme 84).

6.17 Wardrop’s formal synthesis (2005) See (Scheme 85).

6.18 Jacobsen’s total synthesis (2006) See (Scheme 86).

87

88

6. Lactacystin

SCHEME 76

aldol reaction.14

Total synthesis via SnCl4-mediated stereoselective vinylogous Mukaiyama

6.19 Shibasaki’s total synthesis (2006) See (Scheme 87).

6.20 Hayes’s total synthesis via 1,5-CH insertion (2008) See (Scheme 88).

6.23 Inoue’s total synthesis (2015)

SCHEME 77

Total synthesis via Overman rearrangement.15

6.21 Hayes’s formal synthesis (2010) See (Scheme 89).

6.22 Silverman’s total synthesis (2011) See (Scheme 90).

6.23 Inoue’s total synthesis (2015) See (Scheme 91).

89

90

6. Lactacystin

SCHEME 78 Formal synthesis via intramolecular mercurioamidation.16

6.24 Chandrasekhar’s formal synthesis (2019) See (Scheme 92).

6.25 Page’s formal synthesis (2019) See (Scheme 93).

6.26 Poisson’s (L)-omuralide synthesis (2019) See (Scheme 94).

6.26 Poisson’s ()-omuralide synthesis (2019)

SCHEME 79

SCHEME 80

Clasto-lactacystin synthesis via aldol.17

Total synthesis via asymmetric crotylation of aldehyde.18

91

92

6. Lactacystin

SCHEME 81

Approach toward lactacystin via Strecker reaction.19

SCHEME 82

Formal synthesis via radical cyclization.20

6.26 Poisson’s ()-omuralide synthesis (2019)

SCHEME 83 Concise total synthesis of lactacystin.21

93

94

6. Lactacystin

SCHEME 84 Racemic synthesis via diastereoselective aldol reaction.21

SCHEME 85

Formal synthesis via 1,5-CH insertion.22

SCHEME 86

imide.23

Total synthesis via Michael addition between nitrile and b-silyl unsaturated

SCHEME 87

Total synthesis via Strecker reaction.24

96

6. Lactacystin

SCHEME 88 Total synthesis via 1,5-CH insertion.25

6.26 Poisson’s ()-omuralide synthesis (2019)

SCHEME 89

intermediate.26

97

Formal synthesis from hydroxymethyl glutamic acid (HMG) via Shibasaki’s

SCHEME 90

Total synthesis of lactacystin.27

SCHEME 91 Total synthesis via C(sp3)-H functionalizations.28

6.26 Poisson’s ()-omuralide synthesis (2019)

SCHEME 92 Asymmetric formal synthesis of (þ)-lactacystin.29

99

100

6. Lactacystin

SCHEME 93

Formal synthesis of (þ)-lactacystin from L-serine.30

6.26 Poisson’s ()-omuralide synthesis (2019)

101

SCHEME 94 ()-Omuralide synthesis via asymmetric ketene [2 þ 2]-cycloaddition.31

102

6. Lactacystin

References 1. Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y. Lactacystin, a Novel Microbial Metabolite, Induces Neuritogenesis of Neuroblastoma Cells. J. Antibiot. 1991, 44, 113e116. 2. Ciechanover, A. Intracellular Protein Degradation: from a Vague Idea, through the Lysosome and the UbiquitineProteasome System, and onto Human Diseases and Drug Targeting (Nobel Lecture). Angew. Chem. Int. Ed. 2005, 44, 5944e5967. 3. (a) Hefti, F.; Weiner, W. J. Nerve Growth Factor and Alzheimer’s Disease. Ann. Neurol. 1986, 20, 275e281. (b) Doherty, P.; Dickson, J. G.; Flanigan, T. P.; Walsh, F. S. Ganglioside GM1 Does Not Initiate, but Enhances Neurite Regeneration of Nerve Growth Factor-dependent Sensory Neurones. J. Neurochem. 1985, 44, 1259e1265. 4. Dick, L. R.; Cruikshank, A. A.; Grenier, L.; Melandri, F. D.; Nunes, S. L.; Stein, R. L. Mechanistic Studies on the Inactivation of the Proteasome by Lactacystin A Central Role for Clasto-Lactacystin b-Lactone. J. Biol. Chem. 1996, 271, 7273e7276. 5. Fenteany, G.; Schreiber, S. L. Lactacystin, Proteasome Function, and Cell Fate. J. Biol. Chem. 1998, 273, 8545e8548. 6. Dick, L. R.; Cruikshank, A. A.; Destree, A. T.; Grenier, L.; McCormack, T. A.; Melandri, F. D.; Nunes, S. L.; Palombella, V. J.; Parent, L. A.; Plamondon, L. Mechanistic Studies on the Inactivation of the Proteasome by Lactacystin in Cultured Cells. J. Biol. Chem. 1997, 272, 182e188. 7. Takahashi, S.; Uchida, K.; Nakagawa, A.; Miyake, Y.; Kainosho, M.; Matsuzaki, K.; Omura, S. Biosynthesis of Lactacystin. J. Antibiot. 1995, 48, 1015e1020. 8. Corey, E.; Reichard, G. A. Total Synthesis of Lactacystin. J. Am. Chem. Soc. 1992, 114 (26), 10677e10678. 9. Corey, E.; Li, W.; Reichard, G. A. A New Magnesium-Catalyzed Doubly Diastereoselective Anti-aldol Reaction Leads to a Highly Efficient Process for the Total Synthesis of Lactacystin in Quantity. J. Am. Chem. Soc. 1998, 120, 2330e2336. 10. Corey, E.; Li, W.; Nagamitsu, T. An Efficient and Concise Enantioselective Total Synthesis of Lactacystin. Angew. Chem. Int. l Ed. 1998, 37, 1676e1679. 11. Saravanan, P.; Corey, E. A Short, Stereocontrolled, and Practical Synthesis of a-methylomuralide, a Potent Inhibitor of Proteasome Function. J. Org. Chem. 2003, 68 (7), 2760e2764. 12. Corey, E.; Li, W.-D. Z.; Nagamitsu, T.; Fenteany, G. The Structural Requirements for Inhibition of Proteasome Function by the Lactacystin-Derived b-lactone and Synthetic Analogs. Tetrahedron 1999, 55 (11), 3305e3316. 13. Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.; Omura, S.; Smith, A. B., III Total Synthesis of (þ)-lactacystin, the First Non-protein Neurotrophic Factor. J. Am. Chem. Soc.  1993, 115, 5302-5302. Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A. B., Total synthesis of (þ)-lactacystin. J. Am. Chem. Soc. 1996, 118, 35843590. 14. Uno, H.; Baldwin, J. E.; Russell, A. T. Total Synthesis of (þ)-lactacystin from (R)glutamate. J. Am. Chem. Soc. 1994, 116, 2139e2140. 15. Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.; Ogawa, S. Stereoselective Total Synthesis of (þ)-lactacystin from D-Glucose. Tetrahedron 1997, 53 (48), 16287e16298. 16. Kang, S. An Enantiocontrolled Synthesis of a Key Intermediate to (þ)-lactacystin. Chem. Commun. 1998, 18, 1929e1930. 17. Soucy, F.; Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack, T. A.; Adams, J.; Plamondon, L. A Novel and Efficient Synthesis of a Highly Active Analogue of Clasto-Lactacystin b-lactone. J. Am. Chem. Soc. 1999, 121 (43), 9967e9976.

References

103

18. Masse, C. E.; Morgan, A. J.; Adams, J.; Panek, J. S. Syntheses and Biological Evaluation of (þ)-Lactacystin and Analogs. Eur. J. Org Chem. 2000, 2000 (14), 2513e2528. 19. Iwama, S.; Gao, W.-G.; Shinada, T.; Ohfune, Y. Asymmetric Strecker Route toward the Synthesis of the Corey Intermediate of Lactacystin. Synlett 2000, 2000 (11), 1631e1633. 20. Brennan, C. J.; Pattenden, G.; Rescourio, G. Formal Synthesis of (þ)-lactacystin Based on a Novel Radical Cyclisation of an a-ethynyl Substituted Serine. Tetrahedron Lett. 2003, 44 (49), 8757e8760. 21. Ooi, H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.; Hatakeyama, S. A Concise Route to (þ)-lactacystin. J. Org. Chem. 2004, 69 (22), 7765e7768. 22. Wardrop, D. J.; Bowen, E. G. A Formal Synthesis of (þ)-lactacystin. Chem. Commun. 2005, 40, 5106e5108. 23. Balskus, E. P.; Jacobsen, E. N. A, b-Unsaturated b-Silyl Imide Substrates for Catalytic, Enantioselective Conjugate Additions: A Total Synthesis of (þ)-Lactacystin and the Discovery of a New Proteasome Inhibitor. J. Am. Chem. Soc. 2006, 128, 6810e6812. 24. Fukuda, N.; Sasaki, K.; Sastry, T.; Kanai, M.; Shibasaki, M. Catalytic Asymmetric Total Synthesis of (þ)-lactacystin. J. Org. Chem. 2006, 71, 1220e1225. 25. Hayes, C. J.; Sherlock, A. E.; Green, M. P.; Wilson, C.; Blake, A. J.; Selby, M. D.; Prodger, J. C. Enantioselective Total Syntheses of Omuralide, 7-Epi-Omuralide, and (þ)-lactacystin. J. Org. Chem. 2008, 73 (6), 2041e2051. 26. Hameed, A.; Blake, A. J.; Hayes, C. J. An Enantioselective Formal Synthesis of (þ)-lactacystin from Hydroxymethyl Glutamic Acid (HMG). Synlett 2010, (04), 535e538. 27. Gu, W.; Silverman, R. B. Stereospecific Total Syntheses of Proteasome Inhibitors Omuralide and Lactacystin. J. Org. Chem. 2011, 76, 8287e8293. 28. Yoshioka, S.; Nagatomo, M.; Inoue, M. Application of Two Direct C(sp3)-H Functionalizations for Total Synthesis of (þ)-Lactacystin. Org. Lett. 2015, 17 (1), 90e93. 29. Sridhar, C.; Vijaykumar, B. V.; Radhika, L.; Shin, D. S.; Chandrasekhar, S. Asymmetric Formal Synthesis of (þ)-Lactacystin. Eur. J. Org Chem. 2014, 2014, 6707e6712. 30. Page, P. C. B.; Goodyear, R. L.; Chan, Y.; Slawin, A. M.; Allin, S. M. Formal Synthesis of (þ)-lactacystin from L-Serine. RSC Adv. 2019, 9, 30019e30032. 31. Rulliere, P.; Cannillo, A.; Grisel, J.; Cividino, P.; Carret, S.b.; Poisson, J.-F. o. Total Synthesis of Proteasome Inhibitor ()-Omuralide through Asymmetric Ketene [2þ 2]Cycloaddition. Org. Lett. 2018, 20, 4558e4561.

C H A P T E R

7

Salinosporamide A 7.1 Abstract

Salinosporamide is another more potent proteasome inhibitor that was isolated by Fenical et al. from the marine microorganism, which is widely distributed in ocean sediments.1 The natural product inhibits proteolytic activity of proteasome with IC50 value of 1.3 nm.2 Moreover, the salinosporamide A showed activity approximately more than 35 times compared with omuralide, an active form of lactacystin.3 The structural scaffold of the natural product is much closely related to terrestrial microbial product omuralide, as both possess pyrrolidinone fused to a b-lactone.4 The mechanism of action of both salinosporamide A and omuralide inhibits proteasome via the esterification of an N-terminal threonine residue of the 20S proteasome with the electrophilic b-lactone.5 As the proteasome-elevated activity is involved in cancer, proteasome inhibition is a significant area of research for cancer therapy. The significant biological importance and challenge structure feature make salinosporamide an interesting synthetic target for organic chemists.

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106

7. Salinosporamide A

7.2 Corey’s first total synthesis of salinosporamide A (2004) See (Scheme 95).

SCHEME 95

First total enantioselective synthesis of salinosporamide A.6

7.3 Second-generation improved synthesis (2005)

7.3 Second-generation improved synthesis (2005) See (Scheme 96).

SCHEME 96 Synthesis via Kulinkovich reaction.7

107

108

7. Salinosporamide A

7.4 Danishefsky enantioselective synthesis (2005) See (Scheme 97).

SCHEME 97

Total enantioselective synthesis.3

7.6 Lam’s formal synthesis (2008)

7.5 Pattenden racemic synthesis (2006) See (Scheme 98).

SCHEME 98 Synthesis via aldol-type cyclization.8

7.6 Lam’s formal synthesis (2008) See (Scheme 99).

SCHEME 99

Formal synthesis via aldol cyclizationelactonization.9

109

110

7. Salinosporamide A

7.7 Romo’s asymmetric total synthesis (2011) See (Scheme 100).

SCHEME 100 Total synthesis via bis-cyclization.10

7.8 Ling’s formal synthesis (2010)

7.8 Ling’s formal synthesis (2010) See (Scheme 101).

SCHEME 101 Formal synthesis via epoxidation and oxirane ring opening.11

111

112

7. Salinosporamide A

7.9 Fukuyama’s total synthesis (2011) See (Scheme 102).

SCHEME 102 Total synthesis via alkylation with chiral auxiliary and cyclization to core pyrrolidine (a gram scale synthesis).12

7.10 Chida’s total synthesis (2011)

7.10 Chida’s total synthesis (2011) See (Scheme 103).

SCHEME 103 Total synthesis via Overman rearrangement.13

113

114

7. Salinosporamide A

7.11 Lannou’s approach (2012) See (Scheme 104).

SCHEME 104 Approach toward salinosporamide A.14

7.12 Burton’s (L)-formal synthesis (2014) See (Scheme 105).

SCHEME 105 ( )-Formal synthesis oxidative radical cyclization.15

7.13 Gonda’s approach (2016)

7.13 Gonda’s approach (2016) See (Scheme 106). • Synthesized advanced intermediate of salinosporamide A.

• Synthesised advance intermediate of salinosporamide A SCHEME 106 Approach via Overman rearrangement.16

115

116

7. Salinosporamide A

7.14 Burton’s total synthesis (2018) See (Scheme 107).

SCHEME 107 Total synthesis of salinosporamide A.17

C H A P T E R

8

Manzacidins The manzacidins AeC are a family of bromopyrrole alkaloids that are isolated by Kobayashi and coworkers from the Okinawan sponge species.1 The manzacidin D without bromo atom was obtained from coralline demosponge .2 The bromopyrrole members of manzacidin family showed interesting biological activities, i.e., a-adrenoceptor blockers, antagonists of the serotonergic receptor, and actomyosin ATPase; however, the inadequate amount of natural products from natural sources promoted their synthetic studies via novel synthetic methodologies to explore further their biological activities3e5 (Fig. 8).

FIGURE 8 Structures of manzacidins.

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119

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120

8. Manzacidins

8.1 Ohfune’s total synthesis of manzacidin A and C (2000) See (Scheme 108).

NH2 OH

a) Boc-L-Phe-OSu, Et3N b) pTsOH, 2,2-dimethoxypropane c) PdCl2, CuCl, O2, 66% (3 steps)

R2

O

HN Boc

N

R1

H

H O

I) R1 = -CH2-Ph; R2 = H II) R1 = H; R2 = -CH2-Ph

N

H O

Strecker reaction a) TMSCN, ZnCl2, 81% b) O3, MeOH, -78 oC, 94%

O

a) Conc. HCl, 0 °C & then 100 oC

TMSOTf, 2,6-lutidine

O

N

N O

N H

O

NC

H Br

NH2 NH2

b) Boc2O, NaHCO3 c) Me4NOH.5H2O, Boc2O

OH

HO H

HN

d) CH2N2, Et2O, 70% (4 steps) e) LiAlH4, Et2O, 0 °C, 81% f) PDC, DCM, (55%)

CCl3

N H

N

HO

CO2H

H

O

NaH, DMF, 100%

Br HN R2

O

HN Boc

N

R1

O

H O R1 = H; R2 = -CH2-Ph

O

NHBoc H Me

O

NHBoc

a) LiAlH4; b) PDC, DCM, 37% (2 steps)

H

NH HN

MeO2C

CO2H

OH a) Boc2O, Et3N, 80% b) NaOH (0.3 N) c) CH2N2, Et2O 62% (3 steps) Boc

OH H minor

Br Br N H

N

HO

Boc

N H H major

H

O

Manzacidine A Overall yield = 14% Total steps = 14

NHBoc

O a) MeReO3, urea-H2O2, 87% b) conc. HCl, 76% c) i) 10% H2SO4, 120 °C; ii) Boc2O, NaHCO3; iii) Me4NOH-5H2O, Boc2O iv) CH2N2, AcOEt, 79% (4 steps)

TFA, DCM, then CH(OMe)3, conc. HCl, 79% HN

N H

a) TMSOTf, 2,6-lutidine Strecker reaction b) TMSCN, ZnCl2, 87% (2 steps)

N

O

CO2H

CCl3 O

HN

N

O

CO2H N H H O Overall yield = 3.5%; Total steps = 15 Manzacidine C

NaH, DMF, 68%

SCHEME 108 Total synthesis of manzacidin A and C via Strecker reaction.6

121

8.2 Du Bois’ enantioselective manzacidins A and C syntheses (2002)

8.2 Du Bois’ enantioselective manzacidins A and C syntheses (2002) See (Scheme 109).

OH

Rh(cod)2OTf, (R)-Phanephos

CO2Et

a)

OH

Cl

CO2Et

OTBDPS

OTBDPS

Prepared from ethyl glyoxylate

HCO2H, 87% (3:1 ratio to epimer) b) Rh2(OAc)4, PhI(OAc)2, MgO, DCM, 85%

75%

J. Am. Chem. Soc. 2000, 122, 7936-7943

Following the same steps of Manzacidine A synthesis to complete Manzacidine C synthesis

OH

OTBDPS HN N H

H

N H

O CO2Et

a) Boc2O, pyridine b) NaN3, 92% (2 steps)

NH

TBDPSO

HN

25%

S

TBDPSO

CO2H

Boc

HO

HN

N

O O Manzacidine C

O

O

CO2Et

7 steps

Br

O O S NCO

a) H2, Pd/C, then Boc NH NHCHO N-formylbenzotriazole TBDPSO OH H

b) POCl3, 2,6-tBu2-4-MeC5H2N, 73% (2 steps) c) HCl (8M), NaHCO3 99%. Br CO2H N H

CCl3 O

Overall yield = 25% Br Total steps = 9

NaH, DMF, 68%

HN N H

O

O

N3 OH H

N

CO2H H Manzacidine A

SCHEME 109 Enantioselective manzacidins A and C syntheses.7

122

8. Manzacidins

8.3 Mackay’s (±)-manzacidin D synthesis (2004) See (Scheme 110).

SCHEME 110 Racemic (
)-manzacidin D synthesis.8

8.4 Lanter’s manzacidin C synthesis (2005) See (Scheme 111).

SCHEME 111 Manzacidin C synthesis via aza-Mannich reaction of sulfinimines.7

123

8.5 Maruoka’s manzacidins A synthesis (2005)

8.5 Maruoka’s manzacidins A synthesis (2005) See (Scheme 112). N2CHCO2Et

Ti-BINOLate (5 mol%), -40 oC, DCM, 52%

OHC

HN N

CO2Et

OHC

HC(OMe)2, 65% (2 steps) MeO N N O CO2Et

95% ee

HN

N

HO H

HN

N

HO H

HN

Br dr = 85:15 CO2H

N H

CCl3 O

Overall yield = 17%; Total steps = 5

Raney-Ni, H2 iPrOH/H2O

N

HO

CO2H

a) NaBH4; b) PPTS,

CO2Et

Br HN

NaH, DMF, 50% (2 steps)

N H

N

O O

H Manzacidine A

SCHEME 112 Manzacidins A synthesis via 1,3-dipolar cycloaddition.9

CO2H

124

8. Manzacidins

8.6 Deng’s formal synthesis of manzacidin A via tandem conjugate additioneprotonation (2006) See (Scheme 113). OH OAc

O MeS

a) NaN3, 56%, dr = 10:1

N

CN

H (20 mol%)

N Cl

CN MeSOC

Cl H

toluene, 8 days 99%, 93% ee

CN

CN b) TMSCl, MeOH 0 oC, 95% CN N3 MeSOC

a) TBDPSCl, imidazole, 91% CN H

O P O P

P Pt

OH

MeSOC

CO2Me

b) EtOH, 80 oC, 97% dr = 10:1 a) H2, Pd/C, Boc2O, EtOH H2N O N3 68%, 91% ee MeSOC

H 93% ee

CO2Me b) Pd(OAc)4, tBuOH reflux, 83% c) TBAF, THF, 70%, 92% ee

SCHEME 113 Formal additioneprotonation.10

synthesis

of

CO2Me

a) NaBH4, Hg(OAc)2 EtOH, 0 oC, 83%

N3 H

H

H

Boc

NH HN

Boc

HO

OH H

Ohfune's route (2002) Manzacidine A

manzacidin

A

via

tandem

conjugate

8.8 Ohfune’s synthesis of manzacidin B (2007)

8.7 Sibi’s manzacidin A synthesis (2007) See (Scheme 114).

SCHEME 114

Manzacidin A synthesis via 1,3-dipolar cycloaddition.11

8.8 Ohfune’s synthesis of manzacidin B (2007) See (Scheme 115).

SCHEME 115 Synthesis and absolute structure of manzacidin B.12

125

126

8. Manzacidins

Later in 2010, Ohfune et al.13 published corrigendum describing that diasteroisomers (manzacidin B and its form) are incorrectly assigned. The reinvestigation of study leads to revision of stereochemistry, which demonstrates the enantiomer ( form) as correct structure of manzacidin B (4 ,5 ,6 ) (Scheme 116).

SCHEME 116 Revised synthetic scheme.

127

8.9 Leighton’s manzacidin C synthesis (2008)

8.9 Leighton’s manzacidin C synthesis (2008) See (Scheme 117).

HN TBDPSO

tBu

O

S

N Cl Si O O

Me S Ph

a) HCO2H, Ac2O, DCM

AgOTf, C6H6, 40 oC N

O TBDPSO

73% CO2iPr

H

N

NH H

CO2iPr

dr > 20:1, 94% ee b) SmI2, THF, iPrOH, -78 oC, 73% (2 steps)

a) PCl5, DMAP b) conc. HCl, 60 oC

S Br N H

O TBDPSO

Cl

N

O TBDPSO

N H

O

S

H NH HN

CO2iPr

NaH, R.T., 49% (3 steps) Br HN N H

N

O O

H

CO2H

Manzacidine C

Overall yield = 26%; Total steps = 6

SCHEME 117 Manzacidin C synthesis via [3 þ 2] cycloaddition.14

H

O CO2iPr

128

8. Manzacidins

8.10 Ohfune’s manzacidins A and C synthesis (2008) See (Scheme 118).

HO

Boc

HN

steps O

CO2Me

EJOC, 2005, 24, 5127-5143 JACS, 1994, 116, 7405

N

Boc

O (MeO)2P

CHO

HN

HO

HN

O Manzacidine A

CO2H d) N H

a) TBSCl, imidazole b) LiBH4, MeOH c) TEMPO, PhI(OAc)2

d) DBU, 67% (4 steps) NHBoc EJOC, 2005, 24, 5127-5143 O JACS, 1994, 116, 7405 (MeO)2P CO2Me

N H

H2 (0.8 Mpa)

NHBoc

Boc

CO2Me [Rh(I)(COD)-Et-DuPHOS] +OTf(5 mol%), THF, R.T. 95% dr = 13:1 Boc N O NHBoc

NaH, R.T. Cl O

NH HN

TBSO H

H CO2Me

36% (4 steps)

Boc CO2H

H2 (0.8 Mpa) [Rh(I)(COD)-Et-DuPHOS] +OTf(5 mol%), THF, R.T. 95% dr = 13:1 Boc

NH HN

TBSO

Br

O O Manzacidine C

Boc

a) NaOH (1N) b) HCl (6N), DCM c) TFA, CH(OMe)3

Br HN

N

DBU, 36%

Br H

CO2Me

N H

O

a) NaOH (1N) b) TFA, DCM c) TFA, CH(OMe)3

N

O

Boc

CO2Me

Tetrahedron, 1998, 54, 14963-14974 Tetrahedron: Asymmetry, 2001, 12, 949-957

Br N H

NHBoc

CO2H d) N H

NaH, R.T. Cl O

46% (4 steps)

SCHEME 118 Manzacidins A and C synthesis.12

H

Boc CO2H

129

8.11 Mohapatra’s synthesis of manzacidin B (2012)

8.11 Mohapatra’s synthesis of manzacidin B (2012) See (Scheme 119).

Boc

NaH, THF, -78 oC 85% O

N

Boc N EtO2C

OHC

MeO2C

a) DIBAL-H, DCM, -78 oC b) mCPBA, DCM, -20 oC O c) Cl3CCN, DBU, -20 oC

O P O O

O Boc N

Cl3C

Major isomer (Z/E 4:1)

O

NH O SnCl4, 4 Ao MS, -20 oC 59% (4 steps)

Cl3C a) dil HCl, THF a) TEMPO, BAIB, 78% Boc Boc Boc b) Boc2O, NaHCO3 NH HN b) i) TFA, CH(OMe)3, N N O 87% ( 2 steps) O HO OH ii)HCl, R.T. H 83% (2 steps) OH OH Br Br HN N HN N Cl HO N O CO2H H CO2H N H O H H OH O OH NaH, R.T. 36% Manzacidine B (proposed) Boc N EtO2C

O

same steps as described above

Br HN

N

O

CO2H N H H O OH ent-Manzacidine B (proposed) steps as above Br

Ph3P=C-(CH3)CO2Et Boc

Boc N

O

N

HN O

CO2H H O OH Manzacidine B Ohfune's revised structure 2007 N H

MeO2C

OHC

Boc

steps as above N

Br HN

O N H

N

O

H O OH ent-Manzacidine B (proposed)

MeO2C

SCHEME 119

N

O

Revised synthesis of manzacidin B.15

CO2H

130

8. Manzacidins

8.12 Ohfune’s synthesis of manzacidin B (2012) See (Scheme 120).

O NHBoc RO

CHO

Et3N

O NC

N

R = TBS or MOM

tBu N Cu N tBu Cu(tbuSal)2 5 mol% Et3N (5 mol%)

S O O

H N

L Cu

H H

R* O

N O S O H

O R*

O O

OHC confirmed by X-ray analysis HO

AcOH, THF, H2O (3 : 1 : 1), 84% RO

NHBoc

NHBoc O N O

N

S O O

HCl (6N) Br Br HN N H

N

O H O OH Manzacidine B

c) CO2H

N H

R = TBS (minor) R = MOM (major)

Cl O

NaH, 57% (3 steps)

NH2 NH2 HO H OH

CO2H

a) LiOH (1N) b) HCl (6N)

SCHEME 120 Efficient synthesis of manzacidin B.16

8.13 Kawabata’s manzacidin A synthesis (2013)

131

8.13 Kawabata’s manzacidin A synthesis (2013) See (Scheme 121).

SCHEME 121 Manzacidin A synthesis asymmetric intermolecular conjugate.17

132

8. Manzacidins

8.14 Ichikawa’s manzacidins A and C synthesis (2012) See (Scheme 122). a) TBDPSCl, imidazole b) DIBAL, DCM, -78 oC

OH

a) TEMPO, NCS

TBDPSO OH

CO2Me c) Ph3PC(CH3)CO2Et, DCM 92% (3 steps)

Ligand

Et

Et Et

TBDPSO

(S,S)-Et-DuPHOS

BocHN

Boc

C

NCO

Boc

NH HN

O

CO2Me

Boc a) TFA, DCM, R.T. b) HC(OMe)3, TFA 89% (2 steps) N HO O

HN O

N H

O

NH H

Br

Br

OH

NHCbz

f) tBuOH, TMSCl, 57% (6 steps)

CO2Me

TBDPSO

O

d) MeOH, Et3N e) PPh3, CBr4, Et3N, -10 oC NCbz [3,3] sigmatropic rearrangment

OH

obtained from (+)-methyl D-lactate JOC, 2005, 70, 5339

CO2Me N

Cl3C

a) H2, Pd/C b) Toluene, 50 oC 76% (2 steps)

NCbz

NHCbz

a) Boc2O, DMAP b) TBAF, AcOH O c)

CO2Me

Boc

NHCbz

c) H2 (0.6 MPa) Rh[(cod)Ligand]OTf (5 mol%), MeOH, R.T. 98%

P

a) O3, DCM/MeOH -78 oC, 30 min, then Me2S b) NaBH4, -10 oC, 89% (2 steps) BocHN

O (MeO)2P

TMG, DCM CO2Me 74% (2 steps)

Et P

b)

N

CO2H H Manzacidine A

N H

Cl O

46%

NaH, R.T. a) TEMPO, NCS O b) (MeO) P NHCbz 2

c) H2 (0.6 MPa) TMG, DCM CO Me Rh[(cod)Ligand]OTf 2 (5 mol%),56% (3 steps)

TBDPSO

NHCbz CO2Me

Ohfune's route 2000

Boc

Boc NH HN

Following the steps used in Manzacidine A synthesis

Manzacidine C O

O

SCHEME 122 Efficient synthesis of manzacidins A and C.18

CO2H

133

8.15 Inoue’s manzacidin A synthesis (2015)

8.15 Inoue’s manzacidin A synthesis (2015) See (Scheme 123).

Boc N O

OH

isobutyl chloroformate, NMO; (PhTe)2, NaBH4, 0 oC, 79%

Boc Phth

N O

O

TePh

O

O

N

O

OMe

EJOC, 2004,18, 3879-3883

d) Et3B, (Me3Si)3SiH, O (CH2Cl)2 (0.1 M), air, 50 oC, 83% (dr = 1:1)

HN

N

TBDPSO H

CO2H

a) NH2NH2·H2O b) CF3CO2H, CH(OMe)3; aqueous HCl (6 M)

Boc N

CO2Me R = Phth

Br N H O b) NaH, R.T., 33% (3 steps)

N(R)2

O

CCl3

Br HN N H O dr = 1:1

O

N

CO2H H Mazacidine A

SCHEME 123 Manzacidin A synthetic pathway.19

134

8. Manzacidins

8.16 Sakakura’s synthesis of mazacidins A and C (2017) See (Scheme 124).

SCHEME 124 Mazacidins A and C via Henry reaction.20

8.17 Ukaji’s formal synthesis of manzacidin (2017)

135

8.17 Ukaji’s formal synthesis of manzacidin (2017) See (Scheme 125).

SCHEME 125 Manzacidin C via 1,3-dipolar cycloaddition of azomethine imines.21

136

8. Manzacidins

8.18 Renata’s formal synthesis of manzacidin C (2018) See (Scheme 126).

F3C

CH Hydroxylation via a-Ketoglutarate dependent dioxygenase

SO2N3

NH2

(S)

CF3

CO2H

N3

NH2 CO2H

TBADT, 365 nm hn 49%

a) GriE (0.15 mol%) α KG, Fe2+, >95% conversion

lactonization Boc

NH

H

NHBoc

Boc

NH HN

HO O

O

Ohfune's route JACS, 2000, 122, 10708-10709

Boc

b) H2, Pt/C; (Boc)2O; K2CO3, EtOH HO

CO2H

N3 HN

Boc CO2H

Br HN N H

N

O O

H

CO2H

SCHEME 126 Manzacidin C via GriE catalyzed hydroxylation.22

References 1. Kobayashi, J.; Kanda, F.; Ishibashi, M.; Shigemori, H.; Manzacidins, A. C. Novel Tetrahydropyrimidine Alkaloids from the Okinawan Marine Sponge Hymeniacidon Sp. 1991, 4574e4576. 2. Jahn, T.; Ko¨nig, G. M.; Wright, A. D.; Wo¨rheide, G.; Reitner, J.; Manzacidin, D. An Unprecedented Secondary Metabolite from the “Living Fossil” Sponge Astrosclera Willeyana. 1997, 3883e3884. 3. Faulkner, D. J. Marine Natural Products. 1998, 113e158. 4. Ko¨nig, G. M.; Wright, A. D.; Franzblau, S. G. Assessment of Antimycobacterial Activity of a Series of Mainly Marine Derived Natural Products. 2000, 337e342. 5. Hashimoto, T.; Maruoka, K. Syntheses of Manzacidins: a Stage for the Demonstration of Synthetic Methodologies. 2008, 829e835. 6. Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. Total Synthesis and Absolute Structure of Manzacidin A and C. 2000, 10708e10709. 7. Wehn, P. M.; Du Bois, J. Enantioselective Synthesis of the Bromopyrrole Alkaloids Manzacidin A and C by Stereospecific CH Bond Oxidation. 2002, (44), 12950e12951. 8. Drouin, C.; Woo, J. C.; MacKay, D. B.; Lavigne, R. M. Total Synthesis of (
)-manzacidin D. 2004, (39), 7197e7199.

References

137

9. Kano, T.; Hashimoto, T.; Maruoka, K. Enantioselective 1, 3-dipolar Cycloaddition Reaction between Diazoacetates and a-substituted Acroleins: Total Synthesis of Manzacidin A. 2006, 2174e2175. 10. Wang, Y.; Liu, X.; Deng, L. Dual-function Cinchona Alkaloid Catalysis: Catalytic Asymmetric Tandem Conjugate Addition Protonation for the Direct Creation of Nonadjacent Stereocenters. 2006, 3928e3930. 11. Sibi, M. P.; Stanley, L. M.; Soeta, T. Enantioselective 1, 3-dipolar Cycloadditions of Diazoacetates with Electron-Deficient Olefins. 2007, 1553e1556. 12. Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Synthesis and Absolute Structure of Manzacidin B. 2007, 1765e1767. 13. Shinada, T.; Ikebe, E.; Oe, K.; Namba, K.; Kawasaki, M.; Ohfune, Y. Synthesis and Absolute Structure of Manzacidin B. 2010, , 2170-1767. 14. Tran, K.; Lombardi, P. J.; Leighton, J. L. An Efficient Asymmetric Synthesis of Manzacidin C. 2008, 3165e3167. 15. Sankar, K.; Rahman, H.; Das, P. P.; Bhimireddy, E.; Sridhar, B.; Mohapatra, D. K. Practical Syntheses of Proposed and Revised Manzacidin B and Their Congeners. 2012, 1082e1085. 16. Shinada, T.; Oe, K.; Ohfune, Y. Efficient Total Synthesis of Manzacidin B. 2012, 3250e3253. 17. Yoshimura, T.; Kinoshita, T.; Yoshioka, H.; Kawabata, T. Asymmetric Intermolecular Conjugate Addition of Amino Acid Derivatives via Memory of Chirality: Total Synthesis of Manzacidin A. 2013, 864e867. 18. Ichikawa, Y.; Okumura, K.; Matsuda, Y.; Hasegawa, T.; Nakamura, M.; Fujimoto, A.; Masuda, T.; Nakano, K.; Kotsuki, H. Synthesis of Manzacidin A and C: Efficient Construction of Quaternary Carbon Stereocenters Bearing Nitrogen Substituents. 2012, 614e622. 19. Nagatomo, M.; Nishiyama, H.; Fujino, H.; Inoue, M. Decarbonylative Radical Coupling of a-Aminoacyl Tellurides: Single-Step Preparation of g-Amino and a, b-Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A. 2015, 1557e1561. 20. Kudoh, T.; Araki, Y.; Miyoshi, N.; Tanioka, M.; Sakakura, A. Diastereodivergent Henry Reaction for the Stereoselective Construction of Nitrogen-Containing Tetrasubstituted Carbons: Application to Total Synthesis of Manzacidins A and C. 2017, 1760e1763. 21. Tong, T. M. T.; Soeta, T.; Suga, T.; Kawamoto, K.; Hayashi, Y.; Ukaji, Y. Formal Total Synthesis of Manzacidin C Based on Asymmetric 1, 3-Dipolar Cycloaddition of Azomethine Imines. 2017, 1969e1976. 22. Zwick, C. R., III; Renata, H.; Remote, C.eH. Hydroxylation by an a-KetoglutarateDependent Dioxygenase Enables Efficient Chemoenzymatic Synthesis of Manzacidin C and Proline Analogs. 2018, (3), 1165e1169.

C H A P T E R

9

Neooxazolomycin Neooxazolomycin and oxazolomycin A are most well-known members of oxazolomycin natural product family. The compounds were isolated by Uemura’s group in 1985 from the strains of Streptomyces.1 The oxazolomycin family showed in vitro antiviral activity,2 in vivo anticancer activity against p-388 leukemia,3 and broad range antibacterial activity.4 All the members of oxazolomycin family have closely related structure bearing (1) pyroglutamate core (right), (2) dialkene chain (middle) and (3) oxazole-linked fragment (left). The neooxazolomycin has g-lactone in fused bicyclic system in contrast to oxazolomycin, which possessed spirocyclic consisting of b-lactone and g-lactone rings. The key a,a-dialkyl a-amino acid framework in both types of molecules has been constructed via different methodologies in the their synthetic pathways (Fig. 9).

FIGURE 9 Structures of neooxazolomycin and oxazolomycin A.

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00009-3

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© 2021 Elsevier Inc. All rights reserved.

140

9. Neooxazolomycin

9.1 Kende’s first enantioselective total neooxazolomycin synthesis (1990) See (Scheme 127).

SCHEME 127 First enantioselective total neooxazolomycin synthesis.5

9.2 Hatakeyama‘s total neooxazolomycin synthesis (2007)

141

9.2 Hatakeyama‘s total neooxazolomycin synthesis (2007) See (Scheme 128).

SCHEME 128 Neooxazolomycin total synthesis.6

142

9. Neooxazolomycin

9.3 Hatakeyama‘s total oxazolomycin synthesis (2011) See (Scheme 129).

SCHEME 129 Total oxazolomycin synthesis.7

9.4 Pattenden’s approach toward oxazolomycin A and neooxazolomycin synthesis (2007)

143

9.4 Pattenden’s approach toward oxazolomycin A and neooxazolomycin synthesis (2007) The advanced intermediate could be used as precursor to construct the lactoneepyrrolidinone ring systems in oxazolomycin A and neooxazolomycin synthesis (Scheme 130).

SCHEME 130 Synthetic study toward oxazolomycin A and neooxazolomycin synthesis.8

144

9. Neooxazolomycin

9.5 Moloney’s approach toward oxazolomycin (2002) See (Scheme 131).

SCHEME 131 Synthesis of middle fragment of oxazolomycin.9

9.6 Taylor’s formal synthesis of (þ)-neooxazolomycin (2011)

145

9.6 Taylor’s formal synthesis of (D)-neooxazolomycin (2011) See (Scheme 132).

SCHEME 132 Formal synthesis of (þ)-neooxazolomycin.10

146

9. Neooxazolomycin

9.7 Mohapatra‘s approach toward oxazolomycin (2006) See (Scheme 133).

SCHEME 133 Approach toward spirocyclic system of oxazolomycin.10

9.8 Donohoe‘s approach toward pyrrolidinone core of oxazolomycin A (2012)

147

9.8 Donohoe‘s approach toward pyrrolidinone core of oxazolomycin A (2012) See (Scheme 134).

SCHEME 134 Synthetic studies Toward pyrrolidinone core of oxazolomycin A.11

148

9. Neooxazolomycin

References 1. Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.; Katayama, C.; Iwadare, S.; Shizuri, Y.; Mitomo, R.; Nakano, F.; Matsuzaki, A. Structure of Oxazolomycin, a Novel b-lactone Antibiotic. Tetrahedron Lett. 1985, 26, 1073e1076. 2. Tonew, E.; Tonew, M.; Gra¨fe, U.; Zo¨pel, P. On the Antiviral Activity of Diffusomycin (Oxazolomycin). Acta Virol. 1992, 36, 166e172. 3. Takahashi, K.; Kawabata, M.; Uemura, D.; Iwadare, S.; Mitomo, R.; Nakano, F.; Matsuzaki, A. Structure of Neooxazolomycin, an Antitumor Antibiotic. Tetrahedron Lett. 1985, 26, 1077e1078. 4. Zhao, C.; Coughlin, J. M.; Ju, J.; Zhu, D.; Wendt-Pienkowski, E.; Zhou, X.; Wang, Z.; Shen, B.; Deng, Z. Oxazolomycin Biosynthesis in Streptomyces Albus JA3453 Featuring an “Acyltransferase-less” Type I Polyketide Synthase that Incorporates Two Distinct Extender Units. J. Biol. Chem. 2010, 285, 20097e20108. 5. Kende, A. S.; Kawamura, K.; DeVita, R. J. Enantioselective Total Synthesis of Neooxazolomycin. J. Am. Chem. Soc. 1990, 112, 4070e4072. 6. Onyango, E. O.; Tsurumoto, J.; Imai, N.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Total Synthesis of Neooxazolomycin. Angew. Chem. Int. Ed. 2007, 46, 6703e6705. 7. Eto, K.; Yoshino, M.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Total Synthesis of Oxazolomycin A. Org. Lett. 2011, 13, 5398e5401. 8. Bennett, N. J.; Prodger, J. C.; Pattenden, G. A Synthesis of a Common Intermediate to the LactoneePyrrolidinone Ring Systems in Oxazolomycin A and Neooxazolomycin. Tetrahedron 2007, 63, 6216e6231. 9. Wang, Z.; Moloney, M. G. Synthesis of the Middle Fragment of Oxazolomycin. Tetrahedron Lett. 2002, 43, 9629e9632. 10. Bastin, R.; Dale, J. W.; Edwards, M. G.; Papillon, J. P.; Webb, M. R.; Taylor, R. J. Formal Synthesis of (þ)-neooxazolomycin via a Stille Cross-Coupling/deconjugation Route. Tetrahedron 2011, 67, 10026e10044. 11. Donohoe, T. J.; O’Riordan, T. J.; Peifer, M.; Jones, C. R.; Miles, T. J. Asymmetric Synthesis of the Fully Elaborated Pyrrolidinone Core of Oxazolomycin A. Org. Lett. 2012, 14, 5460e5463.

C H A P T E R

10

Sphingofungins 10.1 Abstract Sphingofungins are a family of natural products with potent antifungal properties, isolated by Merck group from the fermentation of Paecilomyces variotii in 1992.1 The sphingofungins possess unique polyhydroxyamino acid moiety and long lipid chain and are like sphingosine compounds that inhibit serine palmitoyltransferase, an enzyme used in the initial step of sphingolipid biosynthesis.2,3 The sphingofungins E and F bear quaternary center along with trans double bond in polyhydroxy amine scaffold and have antifungal activities against several human pathogenic fungi. The significant biological properties with interesting structural features, i.e., presence of a-substituted a-amino acid with trihydroxy alkylated chain make them interesting target for synthesis chemists (Fig. 10).

FIGURE 10

Structures of sphingofungins (E and F).

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00010-X

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© 2021 Elsevier Inc. All rights reserved.

150

10. Sphingofungins

10.2 Kobayashi’s asymmetric synthesis of sphingofungin F (1998) See (Scheme 135). OSiMe3 C6H13CHO + H2C

cat. Yb(OTf)3 (91%)

H13C6

SEt

SEt OH

H13C6

O

(CH2)5CH2Br OMOM

1

O H13C6

2

CH3

H3C

Et3N, TMSCI (97%) H13C6 (CH2)5CH2Br

5, BuLi (89%)

O

H13C6

(CH2)5CH2Br OH

OTMS (CH2)5

TMSO

OBn

3

4

OH

6

H H3C

CH3

O

O

OH

H13C6

(CH2)5

HCL (99%) 7, R1 = OTMS, R2 = H

R1

R2

10, R1 = R2 = O

TBAF (quant.)

H13C6

(CH2)5 R

1

R

OBn

8, R1 = OH, R2 = H

OTMS

TMSO

2

TMSOTf (91%)

Swern oxid. (89%) 9, R1 = R2 = O

11, R1 = R2 = -O-(CH2)2-O-

OTBS

R2 H13C6

OBn

OR3

(CH2)5 R1

i) MMTrCI, Et3N, DMAP ii) LAH iii) TBSCI, imidazole (91%, 3 steps)

OBn

12, R1 = R2 = -O-(CH2)2-O-, R3 = MMT HCOOH (78%)

OTBS 13, R1 = R2 = O, R3 = H

Swern oxid. (>95%)

H13C6

O

(CH2)5 O

OBn

14

CH3 OH H13C6

(CH2)5

OH

OEt

16

OTBS OH H13C6

N

H 3C N BnO

O

TBAF (94%)

(CH2)5 O

CH3

OEt

N

N

H3C N BnO

15

OEt

i) TsOH

OEt BuLi (83%)

N

EtO

CH3

CH3 OEt

ii) NaOH (58%, 2 steps) OH H13C6

(CH2)5 O

OH

O

BnO H3C

BCl3 (72%)

H13C6

NH2

HO H3C

Sphingofungin F

N

+

18

OH

O

20 mol% Sn(OTf)2 + SnO +

OPh

OPh SiMe3O

NH2

NH

CH3 BnO

O OH

(CH2)5 O

17

O

OH

OH OH

87% yield, syn/anti = 97/3, 91% ee (syn)

SiMe3

OBn

SiMe3

H3 C

CH3

O

O

(H3C)2CO TBAF

5

H3 C (95%)

SiMe3

HC

OC(CH3)2

OBn

MeO

Cat. TsOH

OH

CH3

OH DIBAH (83%)

OMe SiMe3

OBn

OBn

SCHEME 135 Asymmetric synthesis of sphingofungin F.4

10.3 Trost’s total synthesis of sphingofungin F (1998)

10.3 Trost’s total synthesis of sphingofungin F (1998) See (Scheme 136).

SCHEME 136 Total synthesis of sphingofungin F.5

151

152

10. Sphingofungins

10.4 Trost’s total synthesis of sphingofungin F (2001) See (Scheme 137).

SCHEME 137 Total synthesis of sphingofungin F.6

10.5 Trost’s total synthesis of sphingofungin E (2001)

10.5 Trost’s total synthesis of sphingofungin E (2001) See (Scheme 138).

SCHEME 138 Total synthesis of sphingofungin E.6

153

154

10. Sphingofungins

10.6 Lin’s total synthesis of sphingofungin F (2000) See (Scheme 139).

SCHEME 139 Total synthesis of sphingofungin F.7

10.7 Shiozaki’s total synthesis of sphingofungin E (2001)

155

10.7 Shiozaki’s total synthesis of sphingofungin E (2001) See (Scheme 140).

SCHEME 140 Total synthesis of sphingofungin E.8

156

10. Sphingofungins

10.8 Lin’s total synthesis of sphingofungin E (2001) See (Scheme 141).

SCHEME 141 Total synthesis of sphingofungin E.9

10.9 Chida’s total synthesis of sphingofungin E (2002)

10.9 Chida’s total synthesis of sphingofungin E (2002) See (Scheme 142).

SCHEME 142 Total synthesis of sphingofungin E from D-Glucose.10

157

158

10. Sphingofungins

10.10 Chida’s total synthesis of sphingofungin E (2002) See (Scheme 143).

SCHEME 143 Total synthesis of sphingofungin E via Overman rearrangement.11

159

10.11 Ham’s total synthesis of sphingofungin F (2002)

10.11 Ham’s total synthesis of sphingofungin F (2002) See (Scheme 144).

a-i) Dess-Martin periodinane, CH2Cl2; ii) CH=CHMgBr, THF, 0 0 C, 70% for two steps TBSO

OH

TBSO CH2

CH2

TBSO

b) Ac2O, pyr., CH2Cl2, 95%

NHBz

c) pd(PPh3)4, K2CO3, CH3CN, 60°C, 87%

OAc

N

O

NHBz Ph O

d-i) TBAF, THF, 99%; ii) RuCL3, K2S2O8, 1M NaOH, CH3CN; iii) CH2N2, Et2O, CH2Cl2, 68% for two steps

O

H3CO

CH3

CH2 N

e) CH3I, KHMDS, HMPA, THF, –78°C, 73%

O

N

Ph

f-i) O3, MeOH, –78°C, then DMS SnBu3 MgBr2-Et2O, -ii) H3 C CH2Cl2, 78% CH3 for two steps OSBT

CH2

H3CO O Ph

OTBS H

Ph

O N

O

g-i) O3, MeOH, –78°C, then DMS; ii) CrCl2, CH3l, THF, 63% for two steps

OTBS H

I

Ph

O

CH3

N O

O

CH3

I

O CH3

O

O

C6H13 O ( )5

h) t-BuLi, –78°C, then ZnCl2, from –78°C to rt, Pd(Ph3)4, THF, 68%

OTBS H

Ph

O

O N O

i) 2N HCl, THF, 80%

CH3

j) 1N NaOH, reflux, 79%

O

OH

OH

H13C6

COOH ( )5 O

NH2 OH

Sphingofungin F

SCHEME 144 Total synthesis of sphingofungin F.12

CH3

160

10. Sphingofungins

10.12 Hayes’s approach toward sphingofungin E (2006)13 See (Scheme 145).

O

CH3

H 3C

N

O

CH3

H3 C

OTBS

Ph3P

Boc

O O

CH3

H 3C

Boc

H2,Pd/C

N

EtOAc (80%)

CH2Cl2

OTBS 2

1

OTBS

3

N2

O

O (69%)

TMS Li

O

TBSO

Boc

N

O

b) NaIO4 (1 equiv.), THF/H2O (80%)

O

O

a) K2OsO4, NMO, acetone/H2O (94%)

O

N–BOC

6

Boc OH OH OTBS N

H 3C H3C

N

OTBS

O

5

CH3 CH3

Boc

H 3C H 3C

d) K2OsO4, NaIO4 (4 equiv.), THF/H2O (63%)

c) NaIO4 (4 equiv.), THF/H2O (96%)

4 e) RuCl3, NaIO4 (5.8 equiv.), CCl4/MeCN/H2O) (88%)

O O

O

HO

O

HO

OH N–BOC N–BOC

O

7

CH3 CH3

O 8

CH3 CH3 f) HCl(conc.), EtOAc then Dowex 50W x 8-200, 2M NH3(aq)(85%)

O HO

O

(Continued)

OH

H 2N

OH

9 (Continued) TBSO

O

g) NaCIO2, H2C=CMe2, TBSO NaH2PO4, t-BuOH

O

O O

h) TMSCHN2, MeOH, PhH N–BOC (75%, 2-steps) 6

O

i) TBAF, THF/H2O/HOAc HO (77%)

O

CH3

O O O

MsO CH3 k) PPh , Et N, CH Cl 3 3 2 2

CH3 N–BOC

11

CH3

CH3

O

CH3 CH3

O O

j) MsCL, Et3N, CH2Cl2

CH3 O N–BOC

N–BOC O

O O

N–BOC 10

13

O

O

CH3 Ph3P

CH3

O CH3

CH3 CH3

12

CH3

l) d,CH2CI2 (61%, 3-steps) OH

OHO OH

H3C Sphingofungin E Cl

H3 C a

i) NH(Me)OMe.HCL, Pyr, 100%

14

H2N OH

O

OH

N(OMe)Me ii) H2C=CH(CH2)6MgBr, H C 74% 2

H 3C

O

O

b

O

H 3C

c

O iii) HO(CH2)2OH, PTSA

H 3C

d

O

iv) K2OsO4.2H2O, NMO, acetone/H2O, then NaIO2/SiO2, DCM, 87% (3-steps)

SCHEME 145 Synthetic studies toward sphingofungin E.

O

10.13 Xu’s total synthesis of sphingofungin F (2010)

10.13 Xu’s total synthesis of sphingofungin F (2010) See (Scheme 146).

SCHEME 146 Total synthesis of sphingofungin F.14

161

162

10. Sphingofungins

10.14 Martinkova´’s total synthesis of sphingofungin E (2010) See (Scheme 147).

SCHEME 147 Total synthesis of a protected form of sphingofungin E.15

10.15 Kan’s total synthesis of sphingofungin E (2013)

163

10.15 Kan’s total synthesis of sphingofungin E (2013) See (Scheme 148).

O MeO2C BocO

OPNP

a) Mn(OAc)3 .2H2O, TBHP, OH EtOAc, 4 Ä molecular sieves, Et3N, (87%). O b) NaBH4, (MeO)3B, MeOH, –78°C (93%, MeO2C dr = 27:1) BocO

1

c) PNPOH, DEAD, Ph3P, toluene.

( )5

( )5

2

m) AZADO, Phl(OAc)2, OMOM OMOM CO2Me CH2Cl2. OMOM HO

O 8

OMOM CN

I

O 9

OMOM OMOM H3 C

( )5

( )5

12

n) aq. NH3, 0°C (59%, three steps) OMOM OMOM CO2Me ( ) ( )5 H3C 5 OMOM OMOM OMOM CONH O 2 CN 10

OMOM O

O OMOM O

CO2Me +

O

OMOM HN

H3C

O

( )5

NH

( )5

O 11

o) PhI-(OCOCF3)2, toluene, 60°C (11/12 = 3:2).

CO2Me OMOM OMOM

p) 6 M HCl, MeOH q) 3 M NaOH, MeoH, 75°C; Amberlite IRC-76 (63%, three steps). O OH OH

O

OH H3 C H 2N OH OH

O Sphingofungin E

SCHEME 148

OH

OMOM OMOM i) MOMCI, /Pr2NEt, CH2CI2 CO2Me + (63% five steps). I OHC OMOM j) O , CH CI ; Me S, –78°C 3 2 2 2 OMOM CHO to r.t 5

OMOM OMOM CO2Me

( )5

( )5

H3C

e) NaH, MeOH, 0°C. f) MOMCI, /Pr2NEt, MOMO 1,2-dichloroethane, 60°C

g) H2, Pd/C, Et3N, EtOAc. MOMO d) BF3.OEt2, CH2Cl2, O CO2Me h) CAN, MeCN/buffer 0°C; TFA (79% two MeO2C O O (pH 7.6), 0°C steps). MOMO recryst. 4 >99% ee 90% ee 3

k) CrCl2, DMF, THF OMOM OMOM CO2Me (61%, two steps). ( ) ( )5 ( ) ( )5 H3C 5 H 2C 5 OMOM O OMOM CHO O 7 6 l) TMSCN, Et3N, CH2Cl2; NH4F, EtOH,0°C.

H 3C

HO

13

Total synthesis of sphingofungin E.16

164

10. Sphingofungins

10.16 Chida’s total synthesis of sphingofungin F (2015) See (Scheme 149).

H3C

CH3

O

O

CH3

O

O

NaBH4, MeOH, 0°C then NalO4

HO

i) Ph3P=CMeCO2Me CH2Cl2, rt, then

CH3

BOMCl, i-Pr2NEt

OH

MeC2O

ii) 80% AcOH aq. 40°C, 87% (2 steps)

HO

MeOH/H2O, rt, 95%

OH

O

H 3C

OBOM OH

O O

CCl3CN, cat DBU cat. ZnCl2

CH3

CH2Cl2, 0°C, 90%

H 2N

O

CCl3

MeC2O

HN H3C

BHT (5 mol%) t-BuPh, 220°C in a sealed tube 67%

OBOM O

CCl3

MeC2O

OBOM OH

O SN2 Reaction

CH3

MeO2C

PBu3, DEAD, toluene, 0°C, 83%

OBOM

cat. OsO4, NMO

O H3C

CH2Cl2, 40°C 83%, dr = 1:1.6

N O

OBOM

N

OH O

Cl3C

Cl3C O

CCl3CO2H, H2O, CH2Cl2, rt; Et3N then Me2C(OMe)2 CSA, rt, 89%

O O

O H C 3

OBOM

NH

Cl3C

Dess-Martin, NaHCO3

O

O

H 3C

CH3

O

Me

I2HC

O

OH C 3 NH O

O CH3

O

O

H3C

CH3

O

CrCl2, DMF, THF, 35°C 68%, E/Z = 6:1 (2 steps)

CHO

H 3C

OH

NH

Me

H 3C

O

CH2Cl2, rt

MeOH, rt 100%

O

O H3C

H2, Pd/C, Et3N

O

i) 80% AcOH aq.40°C, 92% Me

ii) NaOH aq. MeOH 65 0C, 98%

O

OH C 3

O

NH O

13 total steps 6.0% yield H3 C H 3C H2N

O I HC 2

O

CH3

O

COOH OH

CH3 OH

OH

Sphingofungin F

SCHEME 149 Total synthesis of sphingofungin F by orthoamide-type Overman

rearrangement.17

References

165

10.17 Yakura’s total synthesis of sphingofungin E (2017) See (Scheme 150).

SCHEME 150

Total synthesis of sphingofungin E.18

References 1. Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G. L.; Kurtz, M. B.; Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.; Mandala, S. M. Sphingofungins E and F: Novel Serinepalmitoyl Trans-ferase Inhibitors from Paecilomyces Variotii. J. Antibiot. 1992, 45, 1692e1696. 2. Zweerink, M. M.; Edison, A.; Wells, G.; Pinto, W.; Lester, R. Characterization of a Novel, Potent, and Specific Inhibitor of Serine Palmitoyltransferase. J. Biol. Chem. 1992, 267, 25032e25038. 3. Delgado, A.; Casas, J.; Llebaria, A.; Abad, J. L.; Fabrias, G. Inhibitors of Sphingolipid Metabolism Enzymes. Biochim. Biophys. Acta 2006, 1758, 1957e1977. 4. Kobayashi, S.; Furuta, T. Use of Heterocycles as Chiral Ligands and Auxiliaries in Asymmetric Syntheses of Sphingosine, Sphingofungins B and F. Tetrahedron 1998, 54, 10275e10294. 5. Trost, B. M.; Lee, C. B. A New Strategy for the Synthesis of Sphingosine Analogues. Sphingofungin F. J. Am. Chem. Soc. 1998, 120, 6818e6819. 6. Trost, B. M.; Lee, C. gem-Diacetates as Carbonyl Surrogates for Asymmetric Synthesis. Total Syntheses of Sphingofungins E and F. J. Am. Chem. Soc. 2001, 123, 12191e12201.

166

10. Sphingofungins

7. Liu, D.-G.; Wang, B.; Lin, G.-Q. An Efficient and Convenient Approach to the Total Synthesis of Sphingofungin. J. Org. Chem. 2000, 65, 9114e9119. 8. Nakamura, T.; Shiozaki, M. Total Synthesis of Sphingofungin E. Tetrahedron Lett. 2001, 42, 2701e2704. 9. Wang, B.; Yu, X.-m.; Lin, G.-q. The First Total Synthesis of Sphingofungin E and the Determination of Its Stereochemistry. Synlett 2001, 2001 (Special Issue), 0904e0906. 10. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Total Synthesis of Sphingofungin E From D-glucose. Org. Lett. 2002, 4, 151e154. 11. Oishi, T.; Ando, K.; Inomiya, K.; Sato, H.; Iida, M.; Chida, N. Total Synthesis of (þ)-myriocin and ()-sphingofungin E From Aldohexoses Using Overman Rearrangement as the Key Reaction. Bull. Chem. Soc. Jpn. 2002, 75, 1927e1947. 12. Lee, K.-Y.; Oh, C.-Y.; Ham, W.-H. Total Synthesis of Sphingofungin F. Org. Lett. 2002, 4, 4403e4405. 13. Hayes, C. J.; Bradley, D. M.; Thomson, N. M. An Efficient Enantioselective Synthesis of (2R)-Hydroxymethyl Glutamic Acid and an Approach to the (2R)-HydroxymethylSubstituted Sphingofungins. J. Org. Chem. 2006, 71 (7), 2661e2665. 14. Gan, F.-F.; Yang, S.-B.; Luo, Y.-C.; Yang, W.-B.; Xu, P.-F. Total Synthesis of Sphingofungin F Based on Chiral Tricyclic Iminolactone. J. Org. Chem. 2010, 75, 2737e2740. 15. Martinkova´, M.; Gonda, J.; Raschmanova´, J.S.; Slaninkova´, M.; Kucha´r, J. Total Synthesis of a Protected Form of Sphingofungin E Using the [3, 3]-sigmatropic Rearrangement of an Allylic Thiocyanate as the Key Reaction. Carbohydrate Res. 2010, 345, 2427e2437. 16. Ikeuchi, K.; Hayashi, M.; Yamamoto, T.; Inai, M.; Asakawa, T.; Hamashima, Y.; Kan, T. Stereocontrolled Total Synthesis of Sphingofungin E. Europ. J. Org. Chem. 2013, 2013, 6789e6792. 17. Tsuzaki, S.; Usui, S.; Oishi, H.; Yasushima, D.; Fukuyasu, T.; Oishi, T.; Sato, T.; Chida, N. Total Synthesis of Sphingofungin F by Orthoamide-type Overman Rearrangement of an Unsaturated Ester. Org. Lett. 2015, 17, 1704e1707. 18. Noda, N.; Nambu, H.; Fujiwara, T.; Yakura, T. Total Synthesis of Sphingofungin E and 4, 5-Di-epi-sphingofungin E. Chem. Pharm. Bull. 2017, 65 (7), 687e696.

C H A P T E R

11

(
)-FR901483 and TAN1251 (A-D) 11.1 Abstract The immunosuppressant (
)-FR901483 was isolated in 1996 by scientists at the Fujisawa Pharmaceutical Company in 1996 from the fermentation broth of Cladobotryum sp. No. 11231 collect at Iwaki, Japan.1 The structural framework and relative stereochemistry of FR901483 was established via X-ray crystallographic data; however, the absolute configuration of the natural product was demonstrated when Sinder and Lin154 reported the first total synthesis of this molecule. The structural framework of natural product showed that it exhibits a core tricyclic ring that contains 2-azabicyclo[3.3.1]nonane core fused to a pyrrolidine moiety as well as phosphate residue necessary for bioactivity. The natural was found to have promising immunosuppressant activity in vitro and showed significant prolong graft survival time in the rat skin allograft model. Further, the biological studies of FR901483 showed nonspecific immunosuppressive profile that suggests natural product role as antimetabolite by inhibiting adenylosuccinate synthetase and/or adenylosuccinate lyase. The enzymes have important role in de novo adenosine biosynthetic pathway.2 Moreover, the different modes of action FR901483 from the existing immunosuppressants, i.e., cyclosporine A and tacrolimus suggest it an effective therapeutic agent for new drug development (Fig. 11). The structures of TAN1251 alkaloids also exhibit tricyclic ring core that consists of 1,4-diazabicyclo[3.2.1]octane ring and a spiro-fused cyclohexanone ring and side chain isoprenyl unit. This class of natural products was isolated from Penicillium thomii RA-89 at Takeda Chemical Industries Ltd. in Japan.3 The biological profile of these natural products

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00011-1

167

© 2021 Elsevier Inc. All rights reserved.

168

11. (
)-FR901483 and TAN1251 (A-D)

OMe N HO

NHMe

N

N

O

H O (HO) 2 P O

O

HCl

(-)-TAN1251A

(-)-FR901483

N

N N

O

O

N

O

HO O

O

(+)-TAN1251B

(+)-TAN1251C

FIGURE 11

N

N

O (+)-TAN1251D

Structures of FR901483 and TAN1251A-D.

showed TAN1251A and TAN1251B as mydriatic or antispasmodic/antiulcer agents. Moreover, the affinity of TAN1251B showed stronger affinity for muscarinic acetylcholine receptor than atropine, an anticholinergic or antiparasympathetic drug.4

11.2 Proposed biosynthesis of FR901483 and TAN1251 See (Scheme 151).

11.3 Sinder’s total synthesis of (L)-FR901483 (1999) See (Scheme 152).

11.3 Sinder’s total synthesis of (
)-FR901483 (1999)

SCHEME 151 Proposed biosynthesis of FR901483 and TAN1251.5

169

170

11. (
)-FR901483 and TAN1251 (A-D)

SCHEME 152 Total synthesis of (
)-FR901483.6

11.4 Sorensen’s synthesis via oxidative cyclization (2000)

171

11.4 Sorensen’s synthesis via oxidative cyclization (2000) See (Scheme 153).

SCHEME 153 FR901483 synthesis via oxidative cyclization.7

172

11. (
)-FR901483 and TAN1251 (A-D)

11.5 Ciufolini’s synthesis via oxidative cyclization (2001) See (Scheme 154).

SCHEME 154 Synthesis via oxidative cyclization8,9.

11.6 Funk’s total synthesis (2001)

11.6 Funk’s total synthesis (2001) See (Scheme 155).

SCHEME 155 Total synthesis via an amidoacrolein cycloaddition.10

173

174

11. (
)-FR901483 and TAN1251 (A-D)

11.7 Wardrop’s formal synthesis of (±)-desmethylamino FR901483 (2001) See (Scheme 156).

SCHEME 156 Formal Synthesis of ()-Desmethylamino FR901483 Via an N-Methoxy-NAcylnitrenium Ion-Induced Spirocyclization.11

11.8 Fukuyama’s total synthesis (2004)

11.8 Fukuyama’s total synthesis (2004) See (Scheme 157).

SCHEME 157 Stereocontrolled total synthesis.12

175

176

11. (
)-FR901483 and TAN1251 (A-D)

11.9 Brummond’s formal synthesis (2005) See (Scheme 158).

SCHEME 158 Formal synthesis via tandem cationic aza-Cope rearrangement/Mannich

cyclization.13

11.10 Kerr’s total synthesis via ring-opening/annulation reaction (2009)

11.10 Kerr’s total synthesis via ring-opening/annulation reaction (2009) See (Scheme 159).

SCHEME 159 Total synthesis via ring-opening/annulation reaction.14

177

178

11. (
)-FR901483 and TAN1251 (A-D)

11.11 Fukuyama’s intermediate synthesis of FR901483 (2010) See (Scheme 160).

SCHEME 160 Optically active key intermediate of FR901483.15

11.12 Bonjoch’s tricyclic skeleton

179

11.12 Bonjoch’s tricyclic skeleton of FR901483 (2003) See (Scheme 161).

SCHEME 161 Tricyclic skeleton of FR901483 By palladium-catalyzed cyclization.16

180

11. (
)-FR901483 and TAN1251 (A-D)

11.13 Weinreb’s studies toward total synthesis (2006) See (Scheme 162).

SCHEME 162 Studies toward total synthesis.17

11.14 Reissig’s approach toward azaspirane core of FR901483 (2006) See (Scheme 163).

SCHEME 163 Synthetic studies toward azaspirane core of FR901483.18

11.15 Huang’s formal enantioselective synthesis

181

11.15 Huang’s formal enantioselective synthesis of (L)FR901483 (2012) See (Scheme 164).

SCHEME 164 Formal enantioselective synthesis of (
)-FR901483 via one-pot amide reductive bisalkylation method.19

182

11. (
)-FR901483 and TAN1251 (A-D)

11.16 Huang’s enantioselective total syntheses of (L)FR901483 and (D)-8-epi-FR901483 (2013) See (Scheme 165).

11.16 Huang’s enantioselective total syntheses

183

SCHEME 165 Enantioselective total syntheses of (
)-FR901483 and (þ)-8-epi-FR901483.20

184

11. (
)-FR901483 and TAN1251 (A-D)

11.17 Gaunt’s syntheses of (L)-FR901483 and (D)TAN1251C (2019) See (Scheme 166).

SCHEME 166 Syntheses of (
)-FR901483 and (þ)-TAN1251C via photocatalytic olefin hydroaminoalkylation.21

References

185

References 1. Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.; Shigematsu, N.; Izumi, S.; Okuhara, M. FR901483, a Novel Immunosuppressant Isolated from Cladobotryum sp. No. 11231. J. Antibiot. 1996, 49 (1), 37e44. 2. Ruan, Z.; Li, C.; Shen, D.; Huang, S.-H.; Hong, R. FR901483: Synthetic Efficiency Remains a Challenge. Synthesis 2019, 51 (11), 2237e2251. 3. Shirafuji, H.; Tsubotani, S.; Ishimaru, T.; Harada, S. PCT Int. Appl. 1991, WO 91/13,887, 1992. 4. Broadley, K. J.; Kelly, D. R. Muscarinic Receptor Agonists and Antagonists. Molecules 2001, 6 (3), 142e193. 5. Bonjoch, J.; Diaba, F. Synthesis of Immunosuppressant FR901483 and Biogenetically Related TAN1251 Alkaloids. In Studies in Natural Products Chemistry, Vol. 32; Elsevier, 2005; pp 3e60. 6. Snider, B. B.; Lin, H. Total Synthesis of (
)-FR901483. J. Am. Chem. Soc. 1999, 121, 7778e7786. 7. Scheffler, G.; Seike, H.; Sorensen, E. J. An Enantiospecific Synthesis of the Potent Immunosuppressant FR901483. Angew. Chem. Int. Ed. 2000, 39, 4593e4596. 8. Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Total Synthesis of FR901483. Org. Lett. 2001, Vol. 3, 765e767. 9. Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123, 7534e7538. 10. Maeng, J.-H.; Funk, R. L. Total Synthesis of the Immunosuppressant FR901483 via an Amidoacrolein Cycloaddition. Org. Lett. 2001, 3, 1125e1128. 11. Wardrop, D. J.; Zhang, W. N-Methoxy-N-acylnitrenium Ions: Application to the Formal Synthesis of ()-Desmethylamino FR901483. Org. Lett. 2001, 3, 2353e2356. 12. Kan, T.; Fujimoto, T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Stereocontrolled Total Synthesis of Potent Immunosuppressant FR901483. Org. Lett. 2004, 6, 2729e2731. 13. Brummond, K. M.; Hong, S.-P. A Formal Total Synthesis of (
)-FR901483, Using a Tandem Cationic Aza-Cope Rearrangement/mannich Cyclization Approach. J. Org. Chem. 2005, 70, 907e916. 14. Carson, C. A.; Kerr, M. A. Total Synthesis of FR901483. Org. Lett. 2009, 11, 777e779. 15. Ieda, S.; Kan, T.; Fukuyama, T. Synthesis of the Optically Active Key Intermediate of FR901483. Tetrahedron Lett. 2010, 51, 4027e4029. 16. Bonjoch, J.; Diaba, F.z.; Puigbo´, G.; Peidro´, E.; Sole´, D. A New Synthetic Entry to the Tricyclic Skeleton of FR901483 by Palladium-Catalyzed Cyclization of Vinyl Bromides with Ketone Enolates. Tetrahedron Lett. 2003, 44 (46), 8387e8390. 17. Kropf, J. E.; Meigh, I. C.; Bebbington, M. W.; Weinreb, S. M. Studies on a Total Synthesis of the Microbial Immunosuppresive Agent FR901483. J. Org. Chem. 2006, 71, 2046e2055. 18. Kaden, S.; Reissig, H.-U. Efficient Approach to the Azaspirane Core of FR 901483. Org. Lett. 2006, 8, 4763e4766. 19. Huo, H.-H.; Zhang, H.-K.; Xia, X.-E.; Huang, P.-Q. A Formal Enantioselective Total Synthesis of FR901483. Org. Lett. 2012, 14, 4834e4837. 20. Huo, H.-H.; Xia, X.-E.; Zhang, H.-K.; Huang, P.-Q. Enantioselective Total Syntheses of (
)-FR901483 and (þ)-8-Epi-Fr901483. J. Org. Chem. 2013, 78, 455e465. 21. Gaunt, M. J.; Reich, D.; Trowbridge, A. Rapid Syntheses of (
)-FR901483 and (þ)-TAN1251C Enabled by Complexity-generating Photocatalytic Olefin Hydroaminoalkylation. Angew. Chem. 2019, 132 (6), 2276e2281.

C H A P T E R

12

Synthetic approach to the TAN1251 alkaloids 12.1 Kawahara’s total synthesis of TAN1251A (2002) See (Scheme 167).

SCHEME 167 Total synthesis of TAN1251A.1 a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00012-3

187

© 2021 Elsevier Inc. All rights reserved.

188

12. Synthetic approach to the TAN1251 alkaloids

12.2 Kawahara’s total synthesis of (L)-TAN1251A (2002) See (Scheme 168).

SCHEME 168 Total synthesis of (
)-TAN1251A.2

12.3 Wardrop’s formal synthesis of (
)-TAN1251A (2001)

189

12.3 Wardrop’s formal synthesis of (L)-TAN1251A (2001) See (Scheme 169).

SCHEME 169

spirocyclization.3

Formal synthesis of (
)-TAN1251A via nitrenium ioneinduced

190

12. Synthetic approach to the TAN1251 alkaloids

12.4 Snider’s biomimetic total syntheses of TAN1251AeD (2000) See (Scheme 170).

SCHEME 170 Biomimetic total (þ)–TAN1251C, and (þ)–TAN1251D.

syntheses

of

(-)–TAN1251A,

(þ)–TAN1251B,

12.4 Snider’s biomimetic total syntheses of TAN1251AeD (2000)

SCHEME 170 Cont’d.

191

192

12. Synthetic approach to the TAN1251 alkaloids

12.5 Ciufolini’s approach via oxidative cyclization (2001) See (Scheme 171).

SCHEME 171 Synthetic studies via oxidative cyclization.5

12.6 Honda’s formal synthesis (
)-TAN1251A (2002)

193

12.6 Honda’s formal synthesis (L)-TAN1251A (2002) See (Scheme 172).

SCHEME 172 Formal synthesis of enantiopure (
)-TAN1251A via aromatic oxidation.6

194

12. Synthetic approach to the TAN1251 alkaloids

12.7 Honda’s enantiospecific total synthesis of TAN1251C and D (2002) See (Scheme 173).

SCHEME 173 Enantiospecific total synthesis of TAN1251C and TAN1251D via aromatic oxidation reaction of secondary amine.7

12.8 Hayes’s enantioselective total synthesis of (
)-TAN1251A (2000)

195

12.8 Hayes’s enantioselective total synthesis of (L)-TAN1251A (2000) See (Scheme 174).

SCHEME 174 Enantioselective total synthesis of (
)-TAN1251A via alkylidene 1, 5-CH insertion reaction.8

196

12. Synthetic approach to the TAN1251 alkaloids

12.9 Peiqiang’s enantioselective synthesis key core of TAN1251C See (Scheme 175).

SCHEME 175 Enantioselective synthesis Of diazatricyclic core of alkaloid TAN1251C via an iodoaminocyclization reaction.9

12.10 Kan’s total synthesis of TAN1251C (2017)

197

12.10 Kan’s total synthesis of TAN1251C (2017) See (Scheme 176).

SCHEME 176 Total synthesis of TAN1251C via diastereoselective construction of the azaspiro skeleton.10

198

12. Synthetic approach to the TAN1251 alkaloids

References 1. Nagumo, S.; Nishida, A.; Yamazaki, C.; Matoba, A.; Murashige, K.; Kawahara, N. Total Synthesis of Antimuscarinic Alkaloid,()-TAN1251A. Tetrahedron 2002, 58, 4917e4924. Nagumo, S.; Nishida, A.; Yamazaki, C.; Murashige, K.; Kawahara, N., Total synthesis of ()-TAN1251A. Tetrahedron Lett. 39, 1998, 4493e4496. 2. Nagumo, S.; Matoba, A.; Ishii, Y.; Yamaguchi, S.; Akutsu, N.; Nishijima, H.; Nishida, A.; Kawahara, N. Synthesis of (
)-TAN1251A Using 4-Hydroxy-L-Proline as a Chiral Source. Tetrahedron 2002, 58, 9871e9877. 3. Wardrop, D. J.; Basak, A. N-Methoxy-N-acylnitrenium Ions: Application to the Formal Synthesis of (
)-TAN1251A. Org. Lett. 2001, 3, 1053e1056. 4. Snider, B. B.; Lin, H. Biomimetic Total Syntheses of (
)-TAN1251A,(þ)-TAN1251B,(þ)TAN1251C, and (þ)-TAN1251D. Org. Lett. 2000, 2 (5), 643e646. 5. Ousmer, M.; Braun, N. A.; Bavoux, C.; Perrin, M.; Ciufolini, M. A. Total Synthesis of Tricyclic Azaspirane Derivatives of Tyrosine: FR901483 and TAN1251C. J. Am. Chem. Soc. 2001, 123, 7534e7538. 6. Mizutani, H.; Takayama, J.; Soeda, Y.; Honda, T. Facile Synthesis of Enantiopure (
)-TAN1251A. Tetrahedron Lett. 2002, 43, 2411e2414. 7. Mizutani, H.; Takayama, J.; Honda, T. Enantiospecific Total Synthesis of TAN1251C and TAN1251D. Synlett 2005, 2005 (02), 328e330. 8. Auty, J. M.; Churcher, I.; Hayes, C. J. An Enantioselective Formal Total Synthesis of (-)-TAN1251A. Synlett 2004, 2004 (08), 1443e1445. Asari, A.; Hayes, C. J., A Study Towards the Total Synthesis of TAN1251B. Sains Malaysiana 38, 2009, 869e872. 9. Zhang, H.; Lin, Z.; Huang, H.; Huo, H.; Huang, Y.; Ye, J.; Huang, P. Enantioselective Synthesis of the Diazatricyclic Core of Alkaloid TAN1251C via an Iodoaminocyclization Reaction. Chin. J. Chem. 2010, 28, 1717e1724. 10. Nagasaka, Y.; Shintaku, S.; Matsumura, K.; Masuda, A.; Asakawa, T.; Inai, M.; Egi, M.; Hamashima, Y.; Ishikawa, Y.; Kan, T. Total Synthesis of TAN1251C via Diastereoselective Construction of the Azaspiro Skeleton. Org. Lett. 2017, 19, 3839e3842.

C H A P T E R

13

(1S,3R)-1-Aminocyclopentane1,3-diarboxylic acid (ACPD) 13.1 Abstract (1S,3R)-1-Aminocyclopentane-1,3-diarboxylic acid (ACPD) is a conformationally constrained analog of L-glutamate that is used as a chemical messenger in most of excitatory synapses in the central nervous system.1 Most of the excitatory synapses in the central nervous system use glutamate (Glu) as a chemical messenger (Fig. 12). ACPD has therapeutic potential for neurodegenerative disorders and serves as a selective antagonist of metabotropic glutamate receptors (mGluRs), which are coupled with G proteins to mediate various transduction mechanisms.2 Generally, the glutamate receptors have been classified into two main groups termed as iGluRs (ionotropic glutamate receptors) and mGluRs. ACPD serves as a potential candidate for regulation of glutamate receptor function to treat CNS disorders. ACPD has cyclopentane core bearing quaternary center next to nitrogen atom. Interesting biological potential and different methods to build N-bearing quaternary center to complete stereoselective synthesis of ACPD are included in this section.

FIGURE 12 Structure of ACPD. ACPD, (1S,3R)-1-aminocyclopentane-1,3-diarboxylic acid.

?-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00013-5

199

© 2021 Elsevier Inc. All rights reserved.

200

13. (1S,3R)-1-Aminocyclopentane

13.2 Ma’s total synthesis of (1S,3R)-1-aminocyclopentane-1,3diarboxylic acid (1997) See (Scheme 177).

SCHEME 177 Total synthesis of ACPD.3 ACPD, (1S,3R)-1-aminocyclopentane-1,3-

diarboxylic acid.

13.3 Hodgson’s total (1S,3R)-1-aminocyclopentane-1,3diarboxylic acid synthesis via hydroboration See (Scheme 178).

SCHEME

178 Total ACPD synthesis via hydroboration.4 ACPD, (1S,3R)-1-

aminocyclopentane-1,3-diarboxylic acid.

References

201

13.4 Hayes’s total (1S,3R)-1-aminocyclopentane-1,3diarboxylic acid synthesis via 1,5-CH insertion See (Scheme 179).

SCHEME 179 Total ACPD synthesis via 1,5-CH insertion.5 ACPD, (1S,3R)-1-

aminocyclopentane-1,3-diarboxylic acid.

References 1. Pin, J.-P.; Duvoisin, R. The Metabotropic Glutamate Receptors: Structure and Functions. Neuropharmacology 1995, 34, 1e26. 2. Kno¨pfel, T.; Gasparini, F. Metabotropic Glutamate Receptors: Potential Drug Targets. Drug Discov. Today 1996, 1, 103e108. 3. Ma, D.; Ma, J.; Dai, L. Stereospecific Synthesis of (1S, 3R)-1-Aminocyclopentane-1, 3-dicarboxylic Acid, a Selective Agonist of Metabotropic Glutamate Receptors. Tetrahedron: Asymmetry 1997, 8 (6), 825e827. 4. Hodgson, D. M.; Thompson, A. J.; Wadman, S.; Keats, C. J. On the Possibility of Carbamate-Directed Hydroboration. An Approach to the Asymmetric Synthesis of 1-aminocyclopentane-1, 3-dicarboxylic Acid. Tetrahedron 1999, 55 (35), 10815e10834. 5. Bradley, D. M.; Mapitse, R.; Thomson, N. M.; Hayes, C. J. Enantioselective Synthesis of the Excitatory Amino Acid (1 S, 3 R)-1-Aminocyclopentane-1, 3-dicarboxylic Acid. J. Org. Chem. 2002, 67 (22), 7613e7617.

C H A P T E R

14

Tetrodotoxin 14.1 Abstract Tetrodotoxin (TTX) was isolated from puffer fish, used as speciality in Japanese cuisine, in 1909 from the ovaries and livers of fish, while its structure was elucidated in 1964 on the basis of Tsuda, Woodward, and Goto work that reported independently to identify and characterize the compound with polyfunctionalized dioxaadamantane skeleton, a cyclic guanidine containing a hemiaminal moiety with nine contiguous stereogenic centers.1 The TTX was found to be a potent selective blocker of voltage-gated sodium (Naþ) channels.2 In 1970, Nitta et al. determine the absolute stereochemistry of TTS via X-ray crystallographic analysis of one of its derivatives.3 In acidic conditions, TTX exits as inseparable mixture of orthoester and lactone; therefore, the purification of the tetrodotoxin in final steps is a challenging issue. Later, Yasumoto and Yotsu-Yamashita have isolated many natural analogs of TTX from puffer fish and newts.4 Most of these natural derivatives consist of deoxy species and regard as biosynthetic intermediates or metabolites of tetrodotoxin. TTX with its potent biological activity and structure complexity have obtained much attention from chemist community to synthesize it (Fig. 13).

14.2 Du Bois’s stereoselective synthesis of (L)-tetrodotoxin (2003) See (Scheme 180).

a-Tertiary Amines en Route to Natural Products https://doi.org/10.1016/B978-0-12-822262-1.00014-7

203

© 2021 Elsevier Inc. All rights reserved.

204

14. Tetrodotoxin

FIGURE 13

Structures of tetrodotoxin and its naturally occurring analogs.5,6

14.3 Isobe’s first asymmetric total synthesis (2003) See (Scheme 181).

14.4 Isobe’s efficient total synthesis of tetrodotoxin (2004) See (Scheme 182).

14.4 Isobe’s efficient total synthesis of tetrodotoxin (2004)

205

SCHEME 180 Stereoselective synthesis of ()-tetrodotoxin via Rh-catalyzed CeH insertion and stereospecific CeH amination.7

206

14. Tetrodotoxin

SCHEME 180 Cont’d.

14.5 Sato’s stereocontrolled synthesis of (±)-tetrodotoxin (2005) See (Scheme 183).

14.6 Ohfune’s synthesis of (L)-5,6,11-trideoxytetrodotoxin and its 4-epimer (2006) See (Scheme 184).

14.7 Sato’s stereoselective synthesis of tetrodotoxin (2007) See (Scheme 185).

14.7 Sato’s stereoselective synthesis of tetrodotoxin (2007)

207

SCHEME 181 Asymmetric total synthesis via a new route from 2-acetoxy-tri-O-acetyl-Dglucal.8

208

14. Tetrodotoxin

SCHEME 181 Cont’d.

14.8 Nishikawa’s synthesis of (L)-5,11-dideoxytetrodotoxin (2013)12 See (Scheme 186).

14.8 Nishikawa’s synthesis of ()-5,11-dideoxytetrodotoxin (2013)

SCHEME 182 Efficient total synthesis of optically active tetrodotoxin.9

209

210

14. Tetrodotoxin

SCHEME 182 Cont’d.

14.8 Nishikawa’s synthesis of ()-5,11-dideoxytetrodotoxin (2013)

211

SCHEME 183 Stereocontrolled synthesis of ()-tetrodotoxin from myo-inositol.10

212

14. Tetrodotoxin

SCHEME 183 Cont’d.

14.8 Nishikawa’s synthesis of ()-5,11-dideoxytetrodotoxin (2013)

SCHEME 183 Cont’d.

213

214

14. Tetrodotoxin

SCHEME 184 Synthesis of ()-5,6,11-tideoxytetrodotoxin and its 4-epimer.11

14.8 Nishikawa’s synthesis of ()-5,11-dideoxytetrodotoxin (2013)

SCHEME 184 Cont’d.

215

216

14. Tetrodotoxin

SCHEME 185 Tetrodotoxin synthesis from D-glucose.9

14.8 Nishikawa’s synthesis of ()-5,11-dideoxytetrodotoxin (2013)

SCHEME 185 Cont’d.

217

218

14. Tetrodotoxin

SCHEME 186 Synthesis of ()-5,11-dideoxytetrodotoxin.

14.9 Ciufolin’s formal synthesis of ()-tetrodotoxin (2015)

219

14.9 Ciufolin’s formal synthesis of (±)-tetrodotoxin (2015) See (Scheme 187).

SCHEME 187 Formal synthesis of ()-tetrodotoxin via the oxidative amidation.13

220

14. Tetrodotoxin

14.10 Fukuyama’s total synthesis of (L)-tetrodotoxin (2017) See (Scheme 188).

SCHEME 188 Total synthesis of ()-tetrodotoxin.14

References

221

References 1. a) Goto, T.; Kishi, Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21, 2059e2088. b) Tsuda, K.; Ikuma, S.; Kawamura, M.; Tachikawa, R.; Sakai, K.; Tamura, C.; Amakasu, O. Chem. Pharm. Bull. 1964, 12, 1357e1374. c) Woodward, R. B. Pure Appl. Chem. 1964, 9, 49e74. 2. a) Choudhary, G.; Yotsu-Yamashita, M.; Shang, L.; Yasumoto, T.; Dudley, S. C., Jr. Biophys. J. 2003, 84, 287e294. b) Narahashi, T. J. Toxicol. Toxin ReV 2001, 20, 67e84. 3. Furusaki, A.; Tomie, Y.; Nitta, I. Bull. Chem. Soc. Jpn. 1970, 43, 3325. 4. Yotsu-Yamashita, M. J. Toxicol. Toxin Rev. 2001, 20, 51. 5. Yotsu-Yamashita, M. Chemistry of Puffer Fish Toxin. J. Toxicol. Toxin Rev. 2001, 20 (1), 51e66. 6. Nishikawa, T.; Isobe, M. Synthesis of Tetrodotoxin, a Classic But Still Fascinating Natural Product. Chem. Rec. 2013, 13 (3), 286e302. 7. Hinman, A.; Du Bois, J. A Stereoselective Synthesis of ()-Tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 11510e11511. 8. Ohyabu, N.; Nishikawa, T.; Isobe, M. First Asymmetric Total Synthesis of Tetrodotoxin. J. Am. Chem. Soc. 2003, 125, 8798e8805. 9. Nishikawa, T.; Urabe, D.; Isobe, M. An Efficient Total Synthesis of Optically Active Tetrodotoxin. Angew. Chem. Int. Ed. 2004, 43, 4782e4785. 10. Sato, K.-i.; Akai, S.; Sugita, N.; Ohsawa, T.; Kogure, T.; Shoji, H.; Yoshimura, J. Novel and Stereocontrolled Synthesis of ()-Tetrodotoxin From myo-Inositol. J. Org. Chem. 2005, 70 (19), 7496e7504. 11. Umezawa, T.; Hayashi, T.; Sakai, H.; Teramoto, H.; Yoshikawa, T.; Izumida, M.; Tamatani, Y.; Hirose, T.; Ohfune, Y.; Shinada, T. Total Synthesis of ()-5, 6, 11Trideoxytetrodotoxin and its 4-Epimer. Org. Lett. 2006, 8, 4971e4974. 12. Adachi, M.; Imazu, T.; Isobe, M.; Nishikawa, T. An Improved Synthesis of ()-5,11Dideoxytetrodotoxin. J. Org. Chem. 2013, 78, 1699e1705. 13. Xu, S.; Ciufolini, M. A. Formal Synthesis of ()-Tetrodotoxin via the Oxidative Amidation of a Phenol: On the Structure of the Sato lactone. Org. Lett. 2015, 17, 2424e2427. 14. Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of ()-Tetrodotoxin and 11-norTTX-6 (R)-ol. Angew. Chem. 2017, 129, 1571e1574.

Abbreviations (L)-DIPT (COD)2RhCl (DHQ)2AQN (DHQ)2PHAL (dppf)PdCl2 (imd)2C]S (S)-DTBM-SEGPHOS [Pd2(dba3)] AcOH AIBN Ar AZADOL BAIB BINOL Bn BOP BOPCl CAN CbzCl CbzCl Cp2Zr(H)Cl Cp2ZrHCl CSA DABCO DBAD DCC DDQ de DEF DIAD DIBAL DIEA DMAP DMDO DMF DMSO DPPA EDCI EEACE (enzyme)

Diisopropyl tartrate Cyclooctadiene rhodium chloride dimer Hydroquinine anthraquinone-1,4-diyl diether Hydroquinine 1,4-phthalazinediyl diether [1,10 -Bis(diphenylphosphino)ferrocene]-dichloropalladium(II) Carbonyldiimidazole (S)-(þ)-5,50 -Bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phos phino]-4,40 -bi-1,3-benzodioxole Tris(dibenzylideneacetone)dipalladium Acetic acid Azobisisobutyronitrile Aryl 2-Azaadamantane-N-oxyl Bis(acetoxy)iodobenzene 1,10 -Bi-2-naphthol Benzyl (Benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate Bis(2-oxo-3-oxazolidinyl)phosphinic chloride Ceric ammonium nitrate Benzyl Benzyl chloroformate Chloridobis(h5-cyclopentadienyl)-hydridozirconium Bis(cyclopentadienyl)zirconium(IV) chloride hydride Camphor sulfonic acid 1,4-Diazabicyclo[2.2.2]octane Di-tert-butyl azodicarboxylate N,N0 -dicyclohexylcarbodiimide 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Diastereomeric excess N,N-diethylformamide Diisopropyl azodicarboxylate Diisobutylaluminum hydride Diisopropylethylamine 4-Dimethylaminopyridine Dimethyldioxirane Dimethylformamide Dimethyl sulfoxide Diphenylphosphoryl azide N-Ethyl-N0 -(3-dimethylaminopropyl)carbodiimide hydrochloride Electric eel acetylcholinesterase

223

224 Fmoc-Cl HATU HBTU HMPA HOBt HPLC IBX KHMDS LDA LHMDS MeReO3 MOM MOMCl NCS NDMBA NMO Ns NsCl P(2-Fur) PDC Ph3P PhIO PMBBr PMHS PPA PPTS PTS Red-Al TBAB TBAF TBDPS TBS TBSOTf TEMPO Tf2O TFA TFAA TFEOH TIPSOTf TMEDA TMS TOlSH TPAP TPP Ts VO(acac)2

Abbreviations

9-Fluorenylmethoxycarbonyl chloride Hexafluorophosphate azabenzotriazole tetramethyl uronium or 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate Hexamethylphosphoramide Hydroxybenzotriazole High-performance liquid chromatography 2-Iodoxybenzoic acid Potassium hexamethyldisilazide Lithium diisopropylamide Lithium hexamethyldisilazide Methylrhenium trioxide Methoxymethyl acetal Chloromethyl methyl ether N-Chlorosuccinimide 1,3-dimethylbarbituric acid N-methylmorpholine-N-oxide Nosyl (4-nitrobenzenesulfonyl) 4-Nitrobenzenesulfonyl chloride Disodium tetracarbonylferrate Pyridinium dichromate Triphenylphosphine Iodosobenzene 4-Methoxybenzyl bromide Polymethylhydrosiloxane Polyphosphoric acid Pyridinium p-toluenesulfonate p-Toluenesulfonic acid Sodium bis(2-methoxyethoxy)aluminum hydride Tetra-n-butylammonium bromide Tetra-n-butylammonium fluoride tert-Butyldiphenylsilyl tert-Butyldimethylsilyl tert-Butyldimethylsilyl triflate 2,2,6,6-Tetramethyl-1-piperidinyloxy Trifluoromethanesulfonic anhydride Trifluoroacetic acid Trifluoroacetic anhydride Trifluoroethanol Triisopropylsilyl trifluoromethanesulfonate Tetramethylethylenediamine Trimethylsilyl 4-Methylbenzenethiol Tetrapropylammonium perruthenate Triphenylphosphine Tosyl (4-methylbenzenesulfonyl) Vanadyl acetylacetonate

Index Note: ‘Page numbers followed by “f ” indicate figures.’

A

Alkaloids, 1 Altemicidin Bicyclo[3.3.0] framework, 7 Hayakawa’s studies, 9 Kan’s approach, 7 Kende’s first total (e)-altemicidin synthesis, 6 PotierePolonovski rearrangement, 6 Streptomyces sioyaensis, 5 structure, 5f Amathaspiramides AeF Claisen rearrangement, 13 Fukuyama’s total syntheses, 13 Kim’s synthesis, 15 Lee’s synthesis, 15 Ohfune’s, 13 structures, 12f Sun’s synthesis, 15 Tambar’s formal synthesis, 13 Trauner’s first total synthesis, 11 (1S,3R)-1-Aminocyclopentane-1, 3-diarboxylic acid (ACPD) Hayes’s total synthesis, 201 Hodgson’s total synthesis, 200 Ma’s total synthesis, 200 structure, 199f 2-Amino-3-(3-hydroxy-5-methylisoxazole4-ylpropionate (AMPA), 67 Astroscler willeyana, 119 Asymmetric synthesis, 150

B

Beaudry’s (e)-total synthesis, 41 Bicyclo[3.3.0] framework, 7 Bis-cyclization, 110 Bonjoch’s tricyclic skeleton, 179 Brummond’s formal synthesis, 176 Bubnov’s approach, 32 Burton’s (e)-formal synthesis, 114 Burton’s total synthesis, 116

C

Cephalotaxine (CET) Beaudry’s (e)-total synthesis, 41

225

biosynthesis, 20 Bubnov’s approach, 32 Cephalotaxus alkaloids, 19 Cephalotaxus drupacea, 19 Chandrasekhar’s formal total synthesis, 38 DolbyeWeinreb enamine synthesis, 29 El Bialy’s formal synthesis, 25 ester derivatives, 19f Fan’s total synthesis, 39 Fuchs’s total synthesis, 23 furan oxidationetransannular Mannich cyclization, 41 Gin’s synthetic studies, 30 Hanaoka’s first-generation synthesis, 21 Hanaoka’s second-generation formal synthesis, 22 Hayes’s first formal synthesis, 31 Hayes’s second formal synthesis, 32 Hong’s formal synthesis, 37 Huang’s formal synthesis, 36 Ikeda’s formal synthesis, 25 Ikeda’s total racemic synthesis, 23 Ishibashi’s total synthesis, 31 Jiang’s formal synthesis, 35 Kim’s formal (e)-total synthesis, 41 Kuehne’s total synthesis, 22 Li’s formal synthesis, 30 Li’s second-generation formal synthesis, 28 Li’s synthesis, 27e28 Li’s total synthesis, 33 Liu’s formal synthesis, 33 Mariano’s synthesis, 24 Mori’s asymmetric synthesis, 23 Nagasaka’s synthesis, 25, 27 Renaud’s formal synthesis, 34 Royer’s synthesis, 28 Semmelhack’s total synthesis, 20 single-electron transfer (SET)epromoted photocyclization, 24 Stoltz’s formal synthesis, 31 Tietze’s synthetic approach, 26 Transannular cyclization approach, 24 Tu’s formal synthesis, 34

226 Cephalotaxine (CET) (Continued) Weinreb’s first total ()-cephalotaxine synthesis, 20 Yoshida’s formal synthesis, 27 Zhang-Liu’s formal synthesis, 34 Zhang synthesis, 33 Cephalotaxine formal synthesis, 40 Chamberlin’s total synthesis, 68 Chandrasekhar’s formal synthesis, 90 Chida’s total synthesis, 113, 157, 164 1,5-CH insertion reaction, 46 Ciufolini’s approach, 192 Ciufolini’s synthesis, 172 Ciufolin’s formal synthesis, 219 Claisen rearrangement, 13 Corey’s first total synthesis, 83, 106 Corey’s revised synthesis, 83 Corey’s second-generation synthesis, 83 Corey’s synthesis of a-methylomuralide, 83

D

Danishefsky enantioselective synthesis, 108 Deng’s formal synthesis, 124 a,a Disubstituted-a-amino acid, 1e3 DolbyeWeinreb enamine, 29, 40 Donohoe‘s approach, 147 Donohoe’s racemic synthesis, 87 Du Bois’ enantioselective manzacidins, 121 Du Bois’s stereoselective synthesis, 203

E

El Bialy’s formal synthesis, 25 Ester derivatives, 19f Ester enolate Claisen rearrangement (EECR), 62 Eupenicillium shearii, 67

F

Fan’s total synthesis, 39 First total enantioselective synthesis, 106 Formal synthesis aryne insertion reaction, 59 Au-catalyzed [2 + 3] annulation reaction, 60 N-iminium ion cyclization, 58 nitroso-ene cyclization, 57 Pauson-Khand reaction, 55 reductive gem-bis-alkylation, 56 stereoselective radical carboazidation, 53 (e)-FR901483 Bonjoch’s tricyclic skeleton, 179 Brummond’s formal synthesis, 176

Index

Ciufolini’s synthesis, 172 Fukuyama’s intermediate synthesis, 178 Fukuyama’s total synthesis, 175 Funk’s total synthesis, 173 Gaunt’s syntheses, 184 Huang’s enantioselective total syntheses, 182 Huang’s formal enantioselective synthesis, 181 Kerr’s total synthesis, 177 oxidative cyclization, 171 Penicillium thomii, 167e168 proposed biosynthesis, 168 Reissig’s approach, 180 ring-opening/annulation reaction, 177 Sinder’s total synthesis, 168 Sorensen’s synthesis, 171 Wardrop’s formal synthesis, 174 Weinreb’s studies, 180 FriedeleCrafts cyclization, 43, 47 Fuchs’s total synthesis, 23 Fukuyama’s intermediate synthesis, 178 Fukuyama’s total synthesis, 13, 112, 175, 220 Funk’s total synthesis, 173 Furan oxidationetransannular Mannich cyclization, 41, 61

G

Gaunt’s syntheses, 184 Gin’s synthetic studies, 30 Gonda’s approach, 115

H

Ham’s total synthesis, 159 Hanaoka’s first-generation synthesis, 21 Hanaoka’s second-generation formal synthesis, 22 Hatakeyama‘s total oxazolomycin synthesis, 142 Hatakeyama’s total synthesis, 69, 87 Hayakawa’s studies, 9 Hayes’s approach, 160 Hayes’s enantioselective total synthesis, 195 Hayes’s first formal synthesis, 31 Hayes’s formal synthesis, 89 Hayes’s second formal synthesis, 32 Hayes’s total synthesis, 88, 201 Hodgson’s total synthesis, 200 Honda’s enantiospecific total synthesis, 194 Honda’s formal synthesis, 193

Index

Hong’s formal synthesis, 37 Huang’s enantioselective total syntheses, 182 Huang’s formal enantioselective synthesis, 181 Huang’s formal synthesis, 36 Hydroamination/semipinacol rearrangement reaction, 52

I

Ichikawa’s manzacidins A and C synthesis, 132 Ikeda’s formal synthesis, 25 Ikeda’s total racemic synthesis, 23 Inoue’s manzacidin A synthesis, 133 Inoue’s total synthesis, 89 Ishibashi’s total synthesis, 31 Isobe’s efficient total synthesis, 204

J

Jacobsen’s total synthesis, 87 Jiang’s formal synthesis, 35

K

Kaitocephalin 2-amino-3-(3-hydroxy-5-methylisoxazole4-ylpropionate (AMPA), 67 Chamberlin’s total synthesis, 68 Dhavale’s formal synthesis, 77 Eupenicillium shearii, 67 Garner’s synthesis, 76 Hatakeyama’s total synthesis, 69 Kang’s kaitocephalin total synthesis, 72 Kitahara’s total synthesis, 68 Lee’s total synthesis, 78 Ma’s reinvestigation of kaitocephalin, 69 Ohfune’s total enantioselective synthesis, 68e69 reinvestigation, 73 stereocontrolled total synthesis, 71 structures, 67f total enantioselective synthesis, 70 Kang’s kaitocephalin total synthesis, 72 Kan’s approach, 7 Kan’s total synthesis, 163, 197 Kawabata’s manzacidin A synthesis, 131 Kawahara’s total synthesis, 187 Kende’s first enantioselective total neooxazolomycin synthesis, 140 Kende’s first total (e)-altemicidin synthesis, 6 Kerr’s total synthesis, 177 Kim’s formal (e)-total synthesis, 41

227

Kim’s synthesis, 15 Kitahara’s total synthesis, 68 Kobayashi’s asymmetric synthesis, 150 Kuehne’s total synthesis, 22

L

Lactacystin biosynthesis, 82e83 Chandrasekhar’s formal synthesis, 90 1,5-CH insertion, 88 Corey’s first total synthesis, 83 Corey’s revised synthesis, 83 Corey’s second-generation synthesis, 83 Corey’s synthesis of a-methylomuralide, 83 Donohoe’s racemic synthesis, 87 Hatakeyama’s total synthesis, 87 Hayes’s formal synthesis, 89 Hayes’s total synthesis, 88 Inoue’s total synthesis, 89 Jacobsen’s total synthesis, 87 Ohfune synthesis, 86 Page’s formal synthesis, 90 Pattenden’s formal synthesis, 86 Poisson’s (e)-omuralide synthesis, 90 proteasome inhibition, 82f proteasome-related diseases, 81 Shibasaki’s total synthesis, 88 Silverman’s total synthesis, 89 ˜ mura’s (+)-synthesis, 83 Smith-O Streptomyces species, 81 structure, 81f Wardrop’s formal synthesis, 87 Lam’s formal synthesis, 109 Lannou’s approach, 114 Lanter’s manzacidin C synthesis, 122 Lee’s synthesis, 15 Leighton’s manzacidin C synthesis, 127 Ling’s formal synthesis, 111 Lin’s total synthesis, 154, 156 Li’s formal synthesis, 30 Li’s second-generation formal synthesis, 28 Li’s synthesis, 27e28 Li’s total synthesis, 33 Liu’s formal synthesis, 33

M

Mackay’s ()-manzacidin D synthesis, 122 Manzacidins Astroscler willeyana, 119 Deng’s formal synthesis, 124 Du Bois’ enantioselective manzacidins, 121

228 Manzacidins (Continued) Ohfune’s synthesis, 130 revised synthetic scheme, 126 structures, 119f Ukaji’s formal synthesis, 135 Manzacidins A Ichikawa’s synthesis, 132 Inoue’s synthesis, 133 Kawabata’s synthesis, 131 Maruoka’s synthesis, 123 Ohfune’s synthesis, 128 Sakakura’s synthesis, 134 Sibi’s synthesis, 125 Manzacidins B Mohapatra’s synthesis, 129 Ohfune’s synthesis, 125e126 Manzacidins C Ichikawa’s synthesis, 132 Lanter’s synthesis, 122 Leighton’s synthesis, 127 Ohfune’s synthesis, 128 Renata’s formal synthesis, 136 Manzacidins D, Mackay’s ()-manzacidin D synthesis, 122 Mariano’s synthesis, 24 Martinkova’s total synthesis, 162 Maruoka’s manzacidins A synthesis, 123 Ma’s reinvestigation of kaitocephalin, 69 Ma’s total synthesis, 200 Mohapatra‘s approach, 146 Mohapatra’s synthesis manzacidin B, 129 Moloney’s approach, 144 Mori’s asymmetric synthesis, 23

N

Nagasaka’s synthesis, 27 Neooxazolomycin Hatakeyama‘s total oxazolomycin synthesis, 142 Kende’s first enantioselective total neooxazolomycin synthesis, 140 Pattenden’s approach, 143 structures, 139f Taylor’s formal synthesis, 145 Nishikawa’s synthesis, 208

O

Ohfune’s total enantioselective synthesis, 68e69 Ohfune synthesis, 13, 86, 130, 206 manzacidin B, 125e126 Oxazolomycin Donohoe‘s approach, 147

Index

Mohapatra‘s approach, 146 Moloney’s approach, 144 Oxidative cyclization, 171, 192 Oxy-Nazarov cyclization, 52

P

Page’s formal synthesis, 90 Pattenden racemic synthesis, 109 Pattenden’s approach, 143 Pattenden’s formal synthesis, 86 Pd-catalyzed aerobic oxidative heterocyclization chemistry, 43 Peiqiang’s enantioselective synthesis, 196 Penicillium thomii, 167e168 Poisson’s (-)-omuralide synthesis aldehyde, asymmetric crotylation of, 91 aldol, 91 asymmetric formal synthesis, 99 asymmetric ketene, 101 C(sp3)-H functionalizations, 98 1,5-CH insertion, 94 clasto-lactacystin synthesis, 91 concise total synthesis, 93 diastereoselective aldol reaction, 94 formal synthesis, 94 hydroxymethyl glutamic acid (HMG), 97 lactacystin, 92 racemic synthesis, 94 radical cyclization, 92 Strecker reaction, 95 total synthesis, 98 Poisson’s (e)-omuralide synthesis, 90 Proposed biosynthesis, 168 Proteasome inhibition, 82f Proteasome-related diseases, 81

Q

N-quaternary center, 1e3

R

Radical cascade cyclization reactions, 44 Reissig’s approach, 180 Renata’s formal synthesis, manzacidin C, 136 Renaud’s formal synthesis, 34 Revised synthetic scheme, 126 Ring-opening/annulation reaction, 177 Romo’s asymmetric total synthesis, 110 Royer’s synthesis, 28

S

Sakakura’s synthesis, 134 Salinosporamide A

Index

bis-cyclization, 110 Burton’s (e)-formal synthesis, 114 Burton’s total synthesis, 116 Chida’s total synthesis, 113 Corey’s first total synthesis, 106 Danishefsky enantioselective synthesis, 108 first total enantioselective synthesis, 106 Fukuyama’s total synthesis, 112 Gonda’s approach, 115 Lam’s formal synthesis, 109 Lannou’s approach, 114 Ling’s formal synthesis, 111 Pattenden racemic synthesis, 109 Romo’s asymmetric total synthesis, 110 second-generation improved synthesis, 107 Sato’s stereocontrolled synthesis, 206 Sato’s stereoselective synthesis, 206 Second-generation improved synthesis, 107 Second synthetic route, 49 Semmelhack’s total synthesis, 20 Shibasaki’s total synthesis, 88 Shiozaki’s total synthesis, 155 Sibi’s manzacidin A synthesis, 125 Silverman’s total synthesis, 89 Sinder’s total synthesis, 168 Single-electron transfer (SET)epromoted photocyclization, 24 ˜ mura’s (+)-synthesis, 83 Smith-O Snider’s biomimetic total syntheses, 190 Sorensen’s synthesis, 171 Sphingofungins asymmetric synthesis, 150 Chida’s total synthesis, 157, 164 Ham’s total synthesis, 159 Hayes’s approach, 160 Kan’s total synthesis, 163 Kobayashi’s asymmetric synthesis, 150 Lin’s total synthesis, 154, 156 Martinkova’s total synthesis, 162 Shiozaki’s total synthesis, 155 structures, 149f trihydroxy alkylated chain, 149 Trost’s total synthesis, 149 Xu’s total synthesis, 161 Yakura’s total synthesis, 165 Stereocontrolled total synthesis, 71 Stoltz’s formal synthesis, 31 Strain-released rearrangement of N-vinyl-2-arylaziridines, 42 Streptomyces sioyaensis, 5 Streptomyces species, 81

229

Sun’s synthesis, 15 Synthetic organic chemistry, 1

T

Tambar’s formal synthesis, 13 TAN1251 alkaloids, 167e168 Ciufolini’s approach, 192 Gaunt’s syntheses, 184 Hayes’s enantioselective total synthesis, 195 Honda’s enantiospecific total synthesis, 194 Honda’s formal synthesis, 193 Kan’s total synthesis, 197 Kawahara’s total synthesis, 187 oxidative cyclization, 192 Peiqiang’s enantioselective synthesis, 196 proposed biosynthesis, 168 Snider’s biomimetic total syntheses, 190 Wardrop’s formal synthesis, 189 Tandem hydroamination, 52 Taylor’s formal synthesis, 145 a-Tertiary amine alkaloids, 1e3, 2f synthetic organic chemistry, 1 Tetra-substituted carbon center, 1e3 Tetrodotoxin (TTX) Ciufolin’s formal synthesis, 219 Du Bois’s stereoselective synthesis, 203 Fukuyama’s total synthesis, 220 Isobe’s efficient total synthesis, 204 Isobe’s first asymmetric total synthesis, 204 Nishikawa’s synthesis, 208 Ohfune’s synthesis, 206 Sato’s stereocontrolled synthesis, 206 Sato’s stereoselective synthesis, 206 structures, 204f Tietze’s synthetic approach, 26 Total enantioselective synthesis, 70 Transannulation strategies, 51 Trauner’s first total synthesis, 11 Trost’s total synthesis, 149 Tu’s formal synthesis, 34

U

Ukaji’s formal synthesis, 135

W

Wardrop’s formal synthesis, 87, 174, 189 Weinreb’s first total ()-cephalotaxine synthesis, 20 Weinreb’s studies, 180

230 X

Xu’s total synthesis, 161

Y

Yakura’s total synthesis, 165

Index

Yoshida’s formal synthesis, 27

Z

Zhang-Liu’s formal synthesis, 34 Zhang synthesis, 33